Methods and compositions for detecting autoimmune disorders

ABSTRACT

The invention provides methods and compositions useful for detecting autoimmune disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/794,717, filed Mar. 11, 2013, which is a continuation of U.S.application Ser. No. 13/333,775, filed Dec. 21, 2011, now U.S. Pat. No.8,962,249, which is a continuation of U.S. application Ser. No.12/749,524, filed Mar. 30, 2010, now abandoned, which is a continuationof U.S. application Ser. No. 11/739,606, filed Apr. 24, 2007, nowabandoned, claiming priority under 35 USC 119(e) to U.S. ProvisionalApplication No. 60/794,393 filed Apr. 24, 2006, all of which are herebyincorporated herein in their entirety.

TECHNICAL FIELD

The present invention relates generally to the fields of moleculardetermination of autoimmune diseases. More specifically, the inventionconcerns methods and compositions based on unique molecular signaturesassociated with various aspects of autoimmune disorders.

BACKGROUND

A number of autoimmune disorders are now believed to be characterized bythe production of autoantibodies against a variety of self antigens. Forexample, systemic lupus erythematous (SLE) is an autoimmune disease inwhich autoantibodies cause organ damage by binding to host cells andtissues and by forming immune complexes that deposit in vascular tissuesand activate immune cells. Sjogren's syndrome is an autoimmune diseasecharacterized by inflammation in the glands of the body. Otherautoimmune disorders are also commonly found, including but not limitedto IgA nephropathy, psoriasis, rheumatoid arthritis, multiple sclerosis,ankylosing spondylitis, etc.

Interferon alpha (IFN-α) is a Type I interferon strongly implicated inthe etiology of a number of immune disorders, such as SLE. It isbelieved that treatment approaches involving disruption of IFN-αsignaling may be an effective treatment for such disorders. IFN-α levelsare known to be elevated in SLE, and treatment of patients with IFN-αhas been observed to reversibly cause symptoms similar to SLE inrecipients. Numerous other lines of evidence have linked IFN-α and SLE.

The mechanisms by which IFN-α exerts its effects on the transcription ofgenes in target cells has been extensively investigated. The secondmessenger cascade has been determined, cis-regulatory binding sites foractivated transcription factors have been defined, and several studieshave explored what genes' expression is modulated. The mostcomprehensive of these studies have been performed with oligonucleotidemicroarrays, but definitions of interferon response gene expressionprofiles are still not complete, at least in part because until recentlymicroarrays have not contained a very complete set of reporters for thegenes of the human genome, and also because a variety of technicaldifficulties prevented identification of broadly applicable yet simplesets of marker genes that reliably correlate with pathologicalconditions of interest.

One of the most difficult challenges in clinical management ofautoimmune diseases is the accurate and early identification of thediseases in a patient. To this end, it would be highly advantageous tohave molecular-based diagnostic methods that can be used to objectivelyidentify presence and/or extent of disease in a patient. The inventiondescribed herein provides these methods and other benefits.

All references cited herein, including patent applications andpublications, are incorporated by reference in their entirety.

DISCLOSURE OF THE INVENTION

The invention provides methods and compositions for identifyingautoimmune disorders based at least in part on identification of thegene(s) whose expression is associated with presence and/or extent ofsystemic lupus erythematosus (SLE), wherein SLE is in turn aprototypical autoimmune disease whose disease-associated gene signaturesare also applicable in other autoimmune diseases. For example, asdescribed herein, in one embodiment, genes modulated in response tosignaling by IFN-α were identified. Information generated by thisapproach was then tested and modified to develop a concise andquantitative measure of the degree to which cell or tissue samplesexhibit responses characteristic of autoimmune disorders. As shownherein, detection of one or more of specific genes disclosed herein canbe a useful and informative indicator of presence and/or extent ofautoimmune disorders in a patient. Moreover, metrics or equivalentquotients that are indicative of interferon-associated diseasepresentation and/or severity can be generated by appropriatetransformation of biomarker gene expression information. Exemplarytransformations and resultant metrics are disclosed herein, generatedbased on gene expression data that are also disclosed herein.

In one aspect, the invention provides a method comprising determiningwhether a subject comprises a cell that expresses at least 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2and/or 3 at a level greater than the expression level of the respectivegenes in a normal reference sample, wherein presence of said cellindicates that the subject has an autoimmune disorder.

In one aspect, the invention provides a method of predictingresponsiveness of a subject to autoimmune disease therapy, said methodcomprising determining whether the subject comprises a cell thatexpresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to allof the genes listed in Table 1, 2 and/or 3 at a level greater than theexpression level of the respective genes in a normal reference sample,wherein presence of said cell indicates that the subject would beresponsive to the autoimmune disease therapy.

In one aspect, the invention provides a method for monitoring minimalresidual disease in a subject treated for an autoimmune disease, saidmethod comprising determining whether the subject comprises a cell thatexpresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to allof the genes listed in Table 1, 2 and/or 3 at a level greater than theexpression level of the respective genes in a normal reference sample,wherein detection of said cell is indicative of presence of minimalresidual autoimmune disease.

In one aspect, the invention provides a method for detecting anautoimmune disease state in a subject, said method comprisingdetermining whether the subject comprises a cell that expresses at least2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28 or any number up to all of the genes listedin Table 1, 2 and/or 3 at a level greater than the expression level ofthe respective genes in a normal reference sample, wherein detection ofsaid cell is indicative of presence of an autoimmune disease state inthe subject.

In one aspect, the invention provides a method for assessingpredisposition of a subject to develop an autoimmune disorder, saidmethod comprising determining whether the subject comprises a cell thatexpresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to allof the genes listed in Table 1, 2 and/or 3 at a level greater than theexpression level of the respective genes in a normal reference sample,wherein detection of said cell is indicative of a predisposition for thesubject to develop the autoimmune disorder.

In one aspect, the invention provides a method for diagnosing anautoimmune disorder in a subject, said method comprising determiningwhether the subject comprises a cell that expresses at least 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28 or any number up to all of the genes listed in Table 1, 2and/or 3 at a level greater than the expression level of the respectivegenes in a normal reference sample, wherein detection of said cellindicates that the subject has said autoimmune disorder.

In one aspect, the invention provides a method for distinguishingbetween active and inactive disease states (e.g., active and inactiveSLE) in a subject, said method comprising determining whether thesubject comprises a cell that expresses at least 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28 or any number up to all of the genes listed in Table 1, 2 and/or 3 ata level greater than the expression level of the respective genes in anormal reference sample, wherein detection of said cell indicates thatthe subject has the autoimmune disorder in an active state.

In one aspect, the invention provides a method for determining presenceand/or elevation of anti-dsDNA antibodies in a subject, said methodcomprising determining whether the subject comprises a cell thatexpresses at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or any number up to allof the genes listed in Table 1, 2 and/or 3 at a level greater than theexpression level of the respective genes in a normal reference sample,wherein detection of said cell indicates presence and/or elevation ofanti-dsDNA antibodies in the subject.

Methods of the invention provide information useful for determiningappropriate clinical intervention steps, if and as appropriate.Therefore, in one embodiment of a method of the invention, the methodfurther comprises a clinical intervention step based on results of theassessment of the expression of one or more of the genes listed in Table1, 2 and/or 3 (including, e.g., any combination of genes (e.g., thoselisted in Table 4)). For example, appropriate intervention may involveprophylactic and treatment steps, or adjustment(s) of any then-currentprophylactic or treatment steps based on gene expression informationobtained by a method of the invention.

As would be evident to one skilled in the art, in any method of theinvention, while detection of increased expression of a gene wouldpositively indicate a characteristic of a disease (e.g., presence, stageor extent of a disease), non-detection of increased expression of a genewould also be informative by providing the reciprocal characterizationof the disease.

In one aspect, the invention provides a composition comprisingpolynucleotides capable of specifically hybridizing to at least 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28 or any number up to all of the genes listed in Table1, 2 and/or 3, or complements of such genes. In one embodiment, thepolynucleotides are provided as an array, gene chip, or gene set (e.g.,a set of genes or fragments thereof, provided separately or as amixture).

In one aspect, the invention provides a kit comprising a composition theinvention, and instructions for using the composition to detect anautoimmune disorder by determining whether expression of at least 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28 or any number up to all of the genes listed inTable 1, 2 and/or 3 are at a level greater than the expression level ofthe respective genes in a normal reference sample. In one embodiment,the composition of the invention comprises an array/gene chip/gene setcapable of specifically hybridizing to at least 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28 or any number up to all of the genes listed in Table 1, 2 and/or 3.In one embodiment, the composition of the invention comprises nucleicacid molecules encoding at least a portion of a polypeptide encoded by agene listed in Table 1, 2 and/or 3. In one embodiment, the compositionof the invention comprises nucleic acid primers capable of binding toand effecting polymerization (e.g., amplification) of at least a portionof a gene listed in Table 1, 2 and/or 3. In one embodiment, thecomposition of the invention comprises a binding agent (e.g., primer,probe) that specifically detects a gene (or complement thereof) (orcorresponding gene product) listed in Table 1, 2 and/or 3. In oneembodiment, the composition of the invention comprises a binding agentthat specifically binds to at least a portion of a polypeptide encodedby a gene listed in Table 1, 2 and/or 3.

Methods and compositions of the invention may comprise one or more ofthe genes listed in Table 1, 2 and/or 3. If more than one gene isutilized or included in a method or composition of the invention, themore than one gene can be any combination of any number of the genes aslisted (in no particular order) in Table 1, 2 and/or 3. For example, inone embodiment, a combination of genes comprises only two genes that arelisted, namely OAS3 and HERC5. In one embodiment, a combination of genescomprises only three, only four, only five, or only six genes that arelisted. In one embodiment, a combination of genes comprises at leasttwo, at least three, at least four, at least five, or at least six genesthat are listed. In another embodiment, a combination of genes comprisesOAS3, HERC5, and one or more of the other genes listed in Table 1, 2and/or 3. In one embodiment, a gene combination of the inventioncomprises, consists, or consists essentially of a 3-gene combination(Genes 1, 2 and 3) as indicated in Table 4B. In one embodiment, such3-gene combination is indicated as having a Pearson correlation value ofat least about 0.7, or at least about 0.75, or at least about 0.8, or atleast about 0.85, or at least about 0.9, or at least about 0.95, or atleast about 0.97, or at least about 0.98, or at least about 0.99. In oneembodiment, such 3-gene combination comprises (1) IFIT4, OAS1, and MX1;or (2) OASL, CHMP5, and ZBP1; or (3) IFI44L, OASL, and CIG5; or (4)IFI44L, CIG5, and ZBP1; or (5) EPSTI1, TYKI, and MX1; or (6) IFIT4,HERC5, and TYKI; or (7) IFIT4, TYKI, and XIAP; or (8) IFI44L, OASL, andZBP1; or (9) IFI44L, IFIT4, and OASL; or (10) IFI4, OAS1, and IFIT1; or(11) EPSTI1, HERC5, and TYKI; or (12) IFI44L, EPSTI1, and OASL; or (13)IFI44L, EPSTI1, and OAS3; or (14) EPSTI1, TYKI, and IFIT1; or (15) G1P2,SAMD9L, and SP110. In yet another embodiment, a combination of genescomprises one or more of the genes listed in Table 1, 2 and/or 3,further combined with one or more other genes that are not listed inTable 1, 2 and/or 3 (e.g., a gene known to be associated with anautoimmune disease but not associated with induction by interferonsspecifically).

In any of the embodiments of the invention described herein, one or morereference genes (i.e., genes that, when assessed by themselves, are notknown to be indicative of the disease and/or condition of interest) maybe included. Such reference genes may include housekeeping genes. Forexample, suitable reference genes may be housekeeping genes that canserve as reference/control genes indicative of baseline gene expressionlevels in a sample. Thus, for example, in one embodiment, one or moregenes listed in Tables 1, 2, 3 and/or 4 are used in combination with oneor more housekeeping genes such as ribosomal protein L19 (RPL19;NP_000972), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actins(e.g. β-actin), tubulins, hypoxantine phsophoribosyltransferase (HRPT),and other ribosomal proteins/genes (e.g., 28S, 18S).

In one aspect, the invention provides a method of identifying a metricvalue correlated with presence and/or extent of an autoimmune disorderin a subject or sample, said method comprising:

(a) estimating a group of probesets that is collectively associated witha pattern wherein expression of genes represented by the probesets isassociated with a disease characteristic;

(b) generating a weighting factor that weight probesets in accordancewith a scale reflecting extent of match of each individual probeset totrend of the group of probesets, and calculating the correlationcoefficient of each probeset's profile to the mean profile calculated;

(c) determining a scaling factor, wherein the scaling factor is thevalue required to scale individual probesets to 1;

(d) multiplying the scaling factor by the weighting factor to generate acomposite factor;

(e) multiplying a normal blood sample's signatures with the compositefactor, and the averaging the resulting values across both probesets andsamples to generate an average value, and inverting the average value toyield a global scaling factor;

(f) multiplying each weighting factor by the global scaling factor toobtain a vector of scalar values, and multiplying the scalar values byan expression signature from a sample of interest, and averaging theresulting values to yield a single metric that is indicative of degreeof gene expression associated with Type I interferons in the sample.

In one embodiment of the method of the preceding paragraph, in step (a),the group of probesets comprises probesets that include, or clusteraround, the core most-tightly-correlated pair of probesets in subclusterassociated with a disease characteristic.

In one embodiment of the method of the preceding paragraphs, in step(b), the factor is generated by transforming expression data of thegroup of probesets into z-scores comprising mean scaling to 1, base-2log transformation, then scaling to a standard deviation of the mean of1.

In one embodiment of the method of the preceding paragraphs, in step(e), the global scaling factor is useful for transforming output of theaverage of probesets from a sample of interest into a metric, whereinthe metric is 1 if the sample is from a normal, healthy subject.

In one embodiment of the method of any of the preceding paragraphs, thegroup of probesets comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34 or any number up to all of those listed in Table 1, 2and/or 3. In one embodiment, the group of probesets comprises all thoselisted in Table 1, 2 and/or 3.

In one aspect, the invention provides a method comprising comparing afirst metric obtained by a method described herein for a sample obtainedfrom a subject of interest to a reference metric obtained from areference (e.g., normal, healthy, non-diseased) sample, wherein a firstmetric that is higher than a reference metric indicates presence of anautoimmune disorder in the subject of interest.

In one aspect, the invention provides a method of predictingresponsiveness of a subject to autoimmune disease therapy, said methodcomprising comparing a first metric obtained by a method describedherein for a sample obtained from the subject to a reference metricobtained from a reference (e.g., normal, healthy, non-diseased) sample,wherein a first metric that is higher than a reference metric indicatesthe subject would be responsive to the autoimmune disease therapy.

In one aspect, the invention provides a method for monitoring minimalresidual disease in a subject treated for an autoimmune disease, saidmethod comprising comparing a first metric obtained by a methoddescribed herein for a sample obtained from the subject to a referencemetric obtained from a reference (e.g., normal, healthy, non-diseasedand/or untreated) sample, wherein a first metric that is higher than areference metric is indicative of presence of minimal residualautoimmune disease.

In one aspect, the invention provides a method for detecting anautoimmune disease state, said method comprising comparing a firstmetric obtained by a method described herein for a sample from a subjectsuspected of having the autoimmune disease state to a reference metricobtained from a reference (e.g., normal, healthy, non-diseased) sample,wherein a first metric that is higher than a reference metric isindicative of presence of the autoimmune disease state in the subject.

In one aspect, the invention provides a method for assessingpredisposition of a subject to develop an autoimmune disorder, saidmethod comprising comparing a first metric obtained by a methoddescribed herein for a sample obtained from the subject to a referencemetric obtained from a reference (e.g., normal, healthy, non-diseased)sample, wherein a first metric that is higher than a reference metric isindicative of a predisposition for the subject to develop the autoimmunedisorder.

In one aspect, the invention provides a method for diagnosing anautoimmune disorder in a subject, said method comprising comparing afirst metric obtained by a method described herein for a sample obtainedfrom the subject to a reference metric obtained from a reference (e.g.,normal, healthy, non-diseased) sample, wherein a first metric that ishigher than a reference metric indicates that the subject has saidautoimmune disorder.

In one aspect, the invention provides a method for distinguishingbetween active and inactive disease states (e.g., active and inactiveSLE) in a subject, said method comprising comparing a first metricobtained by a method described herein for a sample obtained from thesubject to a reference metric obtained from a reference (e.g., normal,healthy, non-diseased) sample, wherein a first metric that is higherthan a reference metric indicates that the subject has the autoimmunedisorder in an active state.

In one aspect, the invention provides a method for determining presenceand/or elevation of anti-dsDNA antibodies in a subject, said methodcomprising comparing a first metric obtained by a method describedherein for a sample obtained from the subject to a reference metricobtained from a reference (e.g., normal, healthy, non-diseased) sample,wherein a first metric that is higher than a reference metric indicatespresence and/or elevation of anti-dsDNA antibodies in the subject.

In one embodiment, a reference metric is obtained using a methoddescribed herein for a sample from a control sample (e.g., as obtainedfrom a healthy and/or non-diseased and/or untreated tissue, cell and/orsubject).

The steps in the methods for examining expression of one or morebiomarkers may be conducted in a variety of assay formats, includingassays detecting mRNA expression (including but not limited toconverting mRNA to cDNA, optionally followed by nucleic acidamplification), enzymatic assays detecting presence of enzymaticactivity, and immunohistochemistry assays. Optionally, the tissue orcell sample comprises disease tissue or cells.

Still further methods of the invention include methods of treating adisorder in a mammal, such as an immune related disorder, comprisingsteps of obtaining tissue or a cell sample from the mammal, examiningthe tissue or cells for expression (e.g., amount of expression) of oneor more biomarkers, and upon determining said tissue or cell sampleexpresses said one or more biomarkers (e.g., wherein the biomarkers areexpressed in amounts greater than a reference (control) sample),administering an effective amount of a therapeutic agent to said mammal.The steps in the methods for examining expression of one or morebiomarkers may be conducted in a variety of assay formats, includingassays detecting mRNA expression, enzymatic assays detecting presence ofenzymatic activity, and immunohistochemistry assays. Optionally, themethods comprise treating an autoimmune disorder in a mammal.Optionally, the methods comprise administering an effective amount of atargeted therapeutic agent (e.g., an antibody that binds and/or blocksactivity of Type 1 interferons and/or their corresponding receptor(s)),and, optionally, a second therapeutic agent (e.g., steroids, etc.) tosaid mammal.

In some embodiments, biomarkers are selected from those listed in Tables1, 2 and/or 3.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-F. Alignment of a density plot of interferon-induced genes witha 2D hierarchical cluster heatmap of control and SLE patient samplesshows a single region highly enriched in interferon-induced genes.

FIG. 2. IRGM scores from Active SLE patients are significantly higherthan normal controls.

FIG. 3A-B. Examples of SLE patients whose IRGM and anti-dsDNA levels arewell correlated.

FIG. 4. Rho values of Spearman correlation of probes to the IRGsignature reveal the extent of the region containing IRG signal.

FIG. 5. Three-gene combination versus 24-gene combination Pearsoncorrelation illustrated as a histogram.

MODES FOR CARRYING OUT THE INVENTION General Techniques

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of molecular biology (includingrecombinant techniques), microbiology, cell biology, biochemistry, andimmunology, which are within the skill of the art. Such techniques areexplained fully in the literature, such as, “Molecular Cloning: ALaboratory Manual”, second edition (Sambrook et al., 1989);“Oligonucleotide Synthesis” (M. J. Gait, ed., 1984); “Animal CellCulture” (R. I. Freshney, ed., 1987); “Methods in Enzymology” (AcademicPress, Inc.); “Current Protocols in Molecular Biology” (F. M. Ausubel etal., eds., 1987, and periodic updates); “PCR: The Polymerase ChainReaction”, (Mullis et al., eds., 1994).

Primers, oligonucleotides and polynucleotides employed in the presentinvention can be generated using standard techniques known in the art.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Singleton et al., Dictionary ofMicrobiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York,N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanismsand Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992), provideone skilled in the art with a general guide to many of the terms used inthe present application.

DEFINITIONS

The term “array” or “microarray”, as used herein refers to an orderedarrangement of hybridizable array elements, preferably polynucleotideprobes (e.g., oligonucleotides), on a substrate. The substrate can be asolid substrate, such as a glass slide, or a semi-solid substrate, suchas nitrocellulose membrane. The nucleotide sequences can be DNA, RNA, orany permutations thereof.

A “target sequence”, “target nucleic acid” or “target protein”, as usedherein, is a polynucleotide sequence of interest, in which a mutation ofthe invention is suspected or known to reside, the detection of which isdesired. Generally, a “template,” as used herein, is a polynucleotidethat contains the target nucleotide sequence. In some instances, theterms “target sequence,” “template DNA,” “template polynucleotide,”“target nucleic acid,” “target polynucleotide,” and variations thereof,are used interchangeably.

“Amplification,” as used herein, generally refers to the process ofproducing multiple copies of a desired sequence. “Multiple copies” meansat least 2 copies. A “copy” does not necessarily mean perfect sequencecomplementarity or identity to the template sequence. For example,copies can include nucleotide analogs such as deoxyinosine, intentionalsequence alterations (such as sequence alterations introduced through aprimer comprising a sequence that is hybridizable, but notcomplementary, to the template), and/or sequence errors that occurduring amplification.

Expression/amount of a gene or biomarker in a first sample is at a level“greater than” the level in a second sample if the expressionlevel/amount of the gene or biomarker in the first sample is at leastabout 1.5×, 1.75×, 2×, 3×, 4×, 5×, 6×, 7×, 8×, 9× or 10× the expressionlevel/amount of the gene or biomarker in the second sample. Expressionlevels/amounts can be determined based on any suitable criterion knownin the art, including but not limited to mRNA, cDNA, proteins, proteinfragments and/or gene copy. Expression levels/amounts can be determinedqualitatively and/or quantitatively.

“Polynucleotide,” or “nucleic acid,” as used interchangeably herein,refer to polymers of nucleotides of any length, and include DNA and RNA.The nucleotides can be deoxyribonucleotides, ribonucleotides, modifiednucleotides or bases, and/or their analogs, or any substrate that can beincorporated into a polymer by DNA or RNA polymerase. A polynucleotidemay comprise modified nucleotides, such as methylated nucleotides andtheir analogs. If present, modification to the nucleotide structure maybe imparted before or after assembly of the polymer. The sequence ofnucleotides may be interrupted by non-nucleotide components. Apolynucleotide may be further modified after polymerization, such as byconjugation with a labeling component. Other types of modificationsinclude, for example, “caps”, substitution of one or more of thenaturally occurring nucleotides with an analog, internucleotidemodifications such as, for example, those with uncharged linkages (e.g.,methyl phosphonates, phosphotriesters, phosphoamidates, cabamates, etc.)and with charged linkages (e.g., phosphorothioates, phosphorodithioates,etc.), those containing pendant moieties, such as, for example, proteins(e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine,etc.), those with intercalators (e.g., acridine, psoralen, etc.), thosecontaining chelators (e.g., metals, radioactive metals, boron, oxidativemetals, etc.), those containing alkylators, those with modified linkages(e.g., alpha anomeric nucleic acids, etc.), as well as unmodified formsof the polynucleotide(s). Further, any of the hydroxyl groups ordinarilypresent in the sugars may be replaced, for example, by phosphonategroups, phosphate groups, protected by standard protecting groups, oractivated to prepare additional linkages to additional nucleotides, ormay be conjugated to solid supports. The 5′ and 3′ terminal OH can bephosphorylated or substituted with amines or organic capping groupsmoieties of from 1 to 20 carbon atoms. Other hydroxyls may also bederivatized to standard protecting groups. Polynucleotides can alsocontain analogous forms of ribose or deoxyribose sugars that aregenerally known in the art, including, for example,2′-O-methyl-2′-O-allyl, 2′-fluoro- or 2′-azido-ribose, carbocyclic sugaranalogs, α-anomeric sugars, epimeric sugars such as arabinose, xylosesor lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclicanalogs and abasic nucleoside analogs such as methyl riboside. One ormore phosphodiester linkages may be replaced by alternative linkinggroups. These alternative linking groups include, but are not limitedto, embodiments wherein phosphate is replaced by P(O)S(“thioate”), P(S)S(“dithioate”), “(O)NR2 (“amidate”), P(O)R, P(O)OR, CO or CH2(“formacetal”), in which each R or R′ is independently H or substitutedor unsubstituted alkyl (1-20 C) optionally containing an ether (—O—)linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not alllinkages in a polynucleotide need be identical. The precedingdescription applies to all polynucleotides referred to herein, includingRNA and DNA.

“Oligonucleotide,” as used herein, generally refers to short, generallysingle stranded, generally synthetic polynucleotides that are generally,but not necessarily, less than about 200 nucleotides in length. Theterms “oligonucleotide” and “polynucleotide” are not mutually exclusive.The description above for polynucleotides is equally and fullyapplicable to oligonucleotides.

A “primer” is generally a short single stranded polynucleotide,generally with a free 3′-OH group, that binds to a target potentiallypresent in a sample of interest by hybridizing with a target sequence,and thereafter promotes polymerization of a polynucleotide complementaryto the target.

The phrase “gene amplification” refers to a process by which multiplecopies of a gene or gene fragment are formed in a particular cell orcell line. The duplicated region (a stretch of amplified DNA) is oftenreferred to as “amplicon.” Usually, the amount of the messenger RNA(mRNA) produced, i.e., the level of gene expression, also increases inthe proportion of the number of copies made of the particular geneexpressed.

The term “mutation”, as used herein, means a difference in the aminoacid or nucleic acid sequence of a particular protein or nucleic acid(gene, RNA) relative to the wild-type protein or nucleic acid,respectively. A mutated protein or nucleic acid can be expressed from orfound on one allele (heterozygous) or both alleles (homozygous) of agene, and may be somatic or germ line.

To “inhibit” is to decrease or reduce an activity, function, and/oramount as compared to a reference.

The term “3′” generally refers to a region or position in apolynucleotide or oligonucleotide 3′ (downstream) from another region orposition in the same polynucleotide or oligonucleotide. The term “5′”generally refers to a region or position in a polynucleotide oroligonucleotide 5′ (upstream) from another region or position in thesame polynucleotide or oligonucleotide.

“Detection” includes any means of detecting, including direct andindirect detection.

The term “diagnosis” is used herein to refer to the identification of amolecular or pathological state, disease or condition, such as theidentification of an autoimmune disorder. The term “prognosis” is usedherein to refer to the prediction of the likelihood of autoimmunedisorder-attributable disease symptoms, including, for example,recurrence, flaring, and drug resistance, of an autoimmune disease. Theterm “prediction” is used herein to refer to the likelihood that apatient will respond either favorably or unfavorably to a drug or set ofdrugs. In one embodiment, the prediction relates to the extent of thoseresponses. In one embodiment, the prediction relates to whether and/orthe probability that a patient will survive or improve followingtreatment, for example treatment with a particular therapeutic agent,and for a certain period of time without disease recurrence. Thepredictive methods of the invention can be used clinically to maketreatment decisions by choosing the most appropriate treatmentmodalities for any particular patient. The predictive methods of thepresent invention are valuable tools in predicting if a patient islikely to respond favorably to a treatment regimen, such as a giventherapeutic regimen, including for example, administration of a giventherapeutic agent or combination, surgical intervention, steroidtreatment, etc., or whether long-term survival of the patient, followinga therapeutic regimen is likely.

The term “long-term” survival is used herein to refer to survival for atleast 1 year, 5 years, 8 years, or 10 years following therapeutictreatment.

The term “increased resistance” to a particular therapeutic agent ortreatment option, when used in accordance with the invention, meansdecreased response to a standard dose of the drug or to a standardtreatment protocol.

The term “decreased sensitivity” to a particular therapeutic agent ortreatment option, when used in accordance with the invention, meansdecreased response to a standard dose of the agent or to a standardtreatment protocol, where decreased response can be compensated for (atleast partially) by increasing the dose of agent, or the intensity oftreatment.

“Patient response” can be assessed using any endpoint indicating abenefit to the patient, including, without limitation, (1) inhibition,to some extent, of disease progression, including slowing down andcomplete arrest; (2) reduction in the number of disease episodes and/orsymptoms; (3) reduction in lesional size; (4) inhibition (i.e.,reduction, slowing down or complete stopping) of disease cellinfiltration into adjacent peripheral organs and/or tissues; (5)inhibition (i.e. reduction, slowing down or complete stopping) ofdisease spread; (6) decrease of autoimmune response, which may, but doesnot have to, result in the regression or ablation of the disease lesion;(7) relief, to some extent, of one or more symptoms associated with thedisorder; (8) increase in the length of disease-free presentationfollowing treatment; and/or (9) decreased mortality at a given point oftime following treatment.

The term “interferon inhibitor” as used herein refers to a moleculehaving the ability to inhibit a biological function of wild type ormutated Type 1 interferon. Accordingly, the term “inhibitor” is definedin the context of the biological role of Type 1 interferon. In oneembodiment, an interferon inhibitor referred to herein specificallyinhibits cell signaling via the Type 1 interferon/interferon receptorpathway. For example, an interferon inhibitor may interact with (e.g.bind to) interferon alpha receptor, or with a Type 1 interferon whichnormally binds to interferon receptor. In one embodiment, an interferoninhibitor binds to the extracellular domain of interferon alphareceptor. In one embodiment, an interferon inhibitor binds to theintracellular domain of interferon alpha receptor. In one embodiment, aninterferon inhibitor binds to Type 1 interferon. In one embodiment, theType 1 interferon is an interferon alpha subtype. In one embodiment, theType 1 interferon is not interferon beta. In one embodiment, the Type 1interferon is not interferon omega. In one embodiment, interferonbiological activity inhibited by an interferon inhibitor is associatedwith an immune disorder, such as an autoimmune disorder. An interferoninhibitor can be in any form, so long as it is capable of inhibitinginterferon/receptor activity; inhibitors include antibodies (e.g.,monoclonal antibodies as defined hereinbelow), small organic/inorganicmolecules, antisense oligonucleotides, aptamers, inhibitorypeptides/polypeptides, inhibitory RNAs (e.g., small interfering RNAs),combinations thereof, etc.

“Antibodies” (Abs) and “immunoglobulins” (Igs) are glycoproteins havingthe same structural characteristics. While antibodies exhibit bindingspecificity to a specific antigen, immunoglobulins include bothantibodies and other antibody-like molecules which generally lackantigen specificity. Polypeptides of the latter kind are, for example,produced at low levels by the lymph system and at increased levels bymyelomas.

The terms “antibody” and “immunoglobulin” are used interchangeably inthe broadest sense and include monoclonal antibodies (e.g., full lengthor intact monoclonal antibodies), polyclonal antibodies, monovalent,multivalent antibodies, multispecific antibodies (e.g., bispecificantibodies so long as they exhibit the desired biological activity) andmay also include certain antibody fragments (as described in greaterdetail herein). An antibody can be chimeric, human, humanized and/oraffinity matured.

“Antibody fragments” comprise only a portion of an intact antibody,wherein the portion preferably retains at least one, preferably most orall, of the functions normally associated with that portion when presentin an intact antibody. In one embodiment, an antibody fragment comprisesan antigen binding site of the intact antibody and thus retains theability to bind antigen. In another embodiment, an antibody fragment,for example one that comprises the Fc region, retains at least one ofthe biological functions normally associated with the Fc region whenpresent in an intact antibody, such as FcRn binding, antibody half lifemodulation, ADCC function and complement binding. In one embodiment, anantibody fragment is a monovalent antibody that has an in vivo half lifesubstantially similar to an intact antibody. For example, such anantibody fragment may comprise on antigen binding arm linked to an Fcsequence capable of conferring in vivo stability to the fragment.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. Monoclonal antibodies are highly specific, being directedagainst a single antigen. Furthermore, in contrast to polyclonalantibody preparations that typically include different antibodiesdirected against different determinants (epitopes), each monoclonalantibody is directed against a single determinant on the antigen.

The monoclonal antibodies herein specifically include “chimeric”antibodies in which a portion of the heavy and/or light chain isidentical with or homologous to corresponding sequences in antibodiesderived from a particular species or belonging to a particular antibodyclass or subclass, while the remainder of the chain(s) is identical withor homologous to corresponding sequences in antibodies derived fromanother species or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired biological activity (U.S. Pat. No. 4,816,567; and Morrison etal., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).

“Humanized” forms of non-human (e.g., murine) antibodies are chimericantibodies that contain minimal sequence derived from non-humanimmunoglobulin. For the most part, humanized antibodies are humanimmunoglobulins (recipient antibody) in which residues from ahypervariable region of the recipient are replaced by residues from ahypervariable region of a non-human species (donor antibody) such asmouse, rat, rabbit or nonhuman primate having the desired specificity,affinity, and capacity. In some instances, framework region (FR)residues of the human immunoglobulin are replaced by correspondingnon-human residues. Furthermore, humanized antibodies may compriseresidues that are not found in the recipient antibody or in the donorantibody. These modifications are made to further refine antibodyperformance. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the hypervariable loops correspondto those of a non-human immunoglobulin and all or substantially all ofthe FRs are those of a human immunoglobulin sequence. The humanizedantibody optionally will also comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin. For further details, see Jones et al., Nature321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); andPresta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the followingreview articles and references cited therein: Vaswani and Hamilton, Ann.Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc.Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech.5:428-433 (1994).

A “human antibody” is one which possesses an amino acid sequence whichcorresponds to that of an antibody produced by a human and/or has beenmade using any of the techniques for making human antibodies asdisclosed herein. This definition of a human antibody specificallyexcludes a humanized antibody comprising non-human antigen-bindingresidues.

An “affinity matured” antibody is one with one or more alterations inone or more CDRs/HVRs thereof which result in an improvement in theaffinity of the antibody for antigen, compared to a parent antibodywhich does not possess those alteration(s). Preferred affinity maturedantibodies will have nanomolar or even picomolar affinities for thetarget antigen. Affinity matured antibodies are produced by proceduresknown in the art. Marks et al. Bio/Technology 10:779-783 (1992)describes affinity maturation by VH and VL domain shuffling. Randommutagenesis of CDR/HVR and/or framework residues is described by: Barbaset al. Proc Nat. Acad. Sci, USA 91:3809-3813 (1994); Schier et al. Gene169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995);Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al, J.Mol. Biol. 226:889-896 (1992).

The term “Fc region” is used to define the C-terminal region of animmunoglobulin heavy chain which may be generated by papain digestion ofan intact antibody. The Fc region may be a native sequence Fc region ora variant Fc region. Although the boundaries of the Fc region of animmunoglobulin heavy chain might vary, the human IgG heavy chain Fcregion is usually defined to stretch from an amino acid residue at aboutposition Cys226, or from about position Pro230, to the carboxyl-terminusof the Fc region. The Fc region of an immunoglobulin generally comprisestwo constant domains, a CH2 domain and a CH3 domain, and optionallycomprises a CH4 domain. By “Fc region chain” herein is meant one of thetwo polypeptide chains of an Fc region.

The term “cytotoxic agent” as used herein refers to a substance thatinhibits or prevents the function of cells and/or causes destruction ofcells. The term is intended to include radioactive isotopes (e.g. At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³² and radioactiveisotopes of Lu), chemotherapeutic agents, and toxins such as smallmolecule toxins or enzymatically active toxins of bacterial, fungal,plant or animal origin, including fragments and/or variants thereof.

A “blocking” antibody or an “antagonist” antibody is one which inhibitsor reduces biological activity of the antigen it binds. Such blockingcan occur by any means, e.g. by interfering with protein-proteininteraction such as ligand binding to a receptor. In on embodiment,blocking antibodies or antagonist antibodies substantially or completelyinhibit the biological activity of the antigen.

An “autoimmune disease” herein is a non-malignant disease or disorderarising from and directed against an individual's own tissues. Theautoimmune diseases herein specifically exclude malignant or cancerousdiseases or conditions, especially excluding B cell lymphoma, acutelymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hairycell leukemia and chronic myeloblastic leukemia. Examples of autoimmunediseases or disorders include, but are not limited to, inflammatoryresponses such as inflammatory skin diseases including psoriasis anddermatitis (e.g. atopic dermatitis); systemic scleroderma and sclerosis;responses associated with inflammatory bowel disease (such as Crohn'sdisease and ulcerative colitis); respiratory distress syndrome(including adult respiratory distress syndrome; ARDS); dermatitis;meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergicconditions such as eczema and asthma and other conditions involvinginfiltration of T cells and chronic inflammatory responses;atherosclerosis; leukocyte adhesion deficiency; rheumatoid arthritis;systemic lupus erythematosus (SLE) (including but not limited to lupusnephritis, cutaneous lupus); diabetes mellitus (e.g. Type I diabetesmellitus or insulin dependent diabetes mellitis); multiple sclerosis;Reynaud's syndrome; autoimmune thyroiditis; Hashimoto's thyroiditis;allergic encephalomyelitis; Sjogren's syndrome; juvenile onset diabetes;and immune responses associated with acute and delayed hypersensitivitymediated by cytokines and T-lymphocytes typically found in tuberculosis,sarcoidosis, polymyositis, granulomatosis and vasculitis; perniciousanemia (Addison's disease); diseases involving leukocyte diapedesis;central nervous system (CNS) inflammatory disorder; multiple organinjury syndrome; hemolytic anemia (including, but not limited tocryoglobinemia or Coombs positive anemia); myasthenia gravis;antigen-antibody complex mediated diseases; anti-glomerular basementmembrane disease; antiphospholipid syndrome; allergic neuritis; Graves'disease; Lambert-Eaton myasthenic syndrome; pemphigoid bullous;pemphigus; autoimmune polyendocrinopathies; Reiter's disease; stiff-mansyndrome; Behcet disease; giant cell arteritis; immune complexnephritis; IgA nephropathy; IgM polyneuropathies; immunethrombocytopenic purpura (ITP) or autoimmune thrombocytopenia etc.

As used herein, “treatment” refers to clinical intervention in anattempt to alter the natural course of the individual or cell beingtreated, and can be performed either for prophylaxis or during thecourse of clinical pathology. Desirable effects of treatment includepreventing occurrence or recurrence of disease, alleviation of symptoms,diminishment of any direct or indirect pathological consequences of thedisease, decreasing the rate of disease progression, amelioration orpalliation of the disease state, and remission or improved prognosis. Insome embodiments, methods and compositions of the invention are usefulin attempts to delay development of a disease or disorder.

An “effective amount” refers to an amount effective, at dosages and forperiods of time necessary, to achieve the desired therapeutic orprophylactic result. A “therapeutically effective amount” of atherapeutic agent may vary according to factors such as the diseasestate, age, sex, and weight of the individual, and the ability of theantibody to elicit a desired response in the individual. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of the therapeutic agent are outweighed by thetherapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result. Typicallybut not necessarily, since a prophylactic dose is used in subjects priorto or at an earlier stage of disease, the prophylactically effectiveamount will be less than the therapeutically effective amount.

As used herein, the terms “type I interferon” and “human type Iinterferon” are defined as all species of native human and syntheticinterferon which fall within the human and synthetic interferon-a,interferon-ω and interferon-13 classes and which bind to a commoncellular receptor. Natural human interferon-α comprises 23 or moreclosely related proteins encoded by distinct genes with a high degree ofstructural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol.Biol., 33: 251 (1986); J. Interferon Res., 13: 443-444 (1993)). Thehuman IFN-α locus comprises two subfamilies. The first subfamilyconsists of at least 14 functional, non-allelic genes, including genesencoding IFN-αA (IFN-α2), IFN-αB (IFN-α8), IFN-αC (IFN-α10), IFN-αD(IFN-αl), IFN-αE (IFN-α22), IFN-αF (IFN-α21), IFN-αG (IFN-α5), IFN-α16,IFN-α17, IFN-α4, IFN-α6, IFN-α7, and IFN-αH (IFN-α14), and pseudogeneshaving at least 80% homology. The second subfamily, α_(II) or ω,contains at least 5 pseudogenes and 1 functional gene (denoted herein as“IFN-α_(II)1” or “IFN-ω”) which exhibits 70% homology with the IFN-αgenes (Weissmann and Weber (1986)). The human IFN-β is generally thoughtto be encoded by a single copy gene.

As used herein, the terms “first human interferon-α (hIFN-α) receptor”,“IFN-αR”, “hIFNAR1”, “IFNAR1”, and “Uze chain” are defined as the 557amino acid receptor protein cloned by Uze et al., Cell, 60: 225-234(1990), including an extracellular domain of 409 residues, atransmembrane domain of 21 residues, and an intracellular domain of 100residues, as shown in FIG. 5 on page 229 of Uze et al. In oneembodiment, the foregoing terms include fragments of IFNAR1 that containthe extracellular domain (ECD) (or fragments of the ECD) of IFNAR1.

As used herein, the terms “second human interferon-α (hIFN-α) receptor”,“IFN-αβR”, “hIFNAR2”, “IFNAR2”, and “Novick chain” are defined as the515 amino acid receptor protein cloned by Domanski et al., J. Biol.Chem., 37: 21606-21611 (1995), including an extracellular domain of 217residues, a transmembrane domain of 21 residues, and an intracellulardomain of 250 residues, as shown in FIG. 1 on page 21608 of Domanski etal. In one embodiment, the foregoing terms include fragments of IFNAR2that contain the extracellular domain (ECD) (or fragments of the ECD) ofIFNAR2, and soluble forms of IFNAR2, such as IFNAR2 ECD fused to atleast a portion of an immunoglobulin sequence.

The term “housekeeping gene” refers to a group of genes that codes forproteins whose activities are essential for the maintenance of cellfunction. These genes are typically similarly expressed in all celltypes. Housekeeping genes include, without limitation, ribosomal proteinL19 (NP_000972), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Cypl,albumin, actins (e.g. β-actin), tubulins, cyclophilin, hypoxantinephosphoribosyltransferase (HRPT), ribosomal protein L32 (NP_001007075),and ribosomal protein/genes 28S (e.g., Q9Y399) and 18S.

The term “biomarker” as used herein refers generally to a molecule,including a gene, protein, carbohydrate structure, or glycolipid, theexpression of which in or on a mammalian tissue or cell can be detectedby standard methods (or methods disclosed herein) and is predictive,diagnostic and/or prognostic for a mammalian cell's or tissue'ssensitivity to treatment regimes based on inhibition of interferons,e.g. Type 1 interferons. Optionally, the expression of such a biomarkeris determined to be higher than that observed for a control/referencetissue or cell sample. Optionally, for example, the expression of such abiomarker will be determined in a PCR or FACS assay to be at least about5-fold, at least about 10-fold, at least about 20-fold, at least about30-fold, at least about 40-fold, at least about 50-fold, or preferablyat least about 100-fold higher in the test tissue or cell sample thanthat observed for a control tissue or cell sample. Optionally, theexpression of such a biomarker will be determined in an IHC assay toscore at least 2 or higher for staining intensity. Optionally, theexpression of such a biomarker will be determined using a genechip-based assay.

An “IRG” or “interferon response gene” or “interferon responsive gene”,as used herein, refers to one or more of the genes, and correspondinggene products, listed in Table 1, 2, 3 and/or 4. As shown herein,aberrant expression levels/amounts of one or more of these genes arecorrelated with a variety of autoimmune disorders. As would be evidentto one skilled in the art, depending on context, the term IRG can referto nucleic acid (e.g., genes) or polypeptides (e.g., proteins) havingthe designation or unique identifier listed in Table 1, 2, 3 and/or 4.

The term “sample”, as used herein, refers to a composition that isobtained or derived from a subject of interest that contains a cellularand/or other molecular entity that is to be characterized and/oridentified, for example based on physical, biochemical, chemical and/orphysiological characteristics. For example, the phrase “disease sample”and variations thereof refers to any sample obtained from a subject ofinterest that would be expected or is known to contain the cellularand/or molecular entity that is to be characterized.

By “tissue or cell sample” is meant a collection of similar cellsobtained from a tissue of a subject or patient. The source of the tissueor cell sample may be solid tissue as from a fresh, frozen and/orpreserved organ or tissue sample or biopsy or aspirate; blood or anyblood constituents; bodily fluids such as cerebral spinal fluid,amniotic fluid, peritoneal fluid, or interstitial fluid; cells from anytime in gestation or development of the subject. The tissue sample mayalso be primary or cultured cells or cell lines. Optionally, the tissueor cell sample is obtained from a disease tissue/organ. The tissuesample may contain compounds which are not naturally intermixed with thetissue in nature such as preservatives, anticoagulants, buffers,fixatives, nutrients, antibiotics, or the like. A “reference sample”,“reference cell”, or “reference tissue”, as used herein, refers to asample, cell or tissue obtained from a source known, or believed, not tobe afflicted with the disease or condition for which a method orcomposition of the invention is being used to identify. In oneembodiment, a reference sample, reference cell or reference tissue isobtained from a healthy part of the body of the same subject or patientin whom a disease or condition is being identified using a compositionor method of the invention. In one embodiment, a reference sample,reference cell or reference tissue is obtained from a healthy part ofthe body of an individual who is not the subject or patient in whom adisease or condition is being identified using a composition or methodof the invention.

For the purposes herein a “section” of a tissue sample is meant a singlepart or piece of a tissue sample, e.g. a thin slice of tissue or cellscut from a tissue sample. It is understood that multiple sections oftissue samples may be taken and subjected to analysis according to thepresent invention, provided that it is understood that the presentinvention comprises a method whereby the same section of tissue sampleis analyzed at both morphological and molecular levels, or is analyzedwith respect to both protein and nucleic acid.

By “correlate” or “correlating” is meant comparing, in any way, theperformance and/or results of a first analysis or protocol with theperformance and/or results of a second analysis or protocol. Forexample, one may use the results of a first analysis or protocol incarrying out a second protocols and/or one may use the results of afirst analysis or protocol to determine whether a second analysis orprotocol should be performed. With respect to the embodiment of geneexpression analysis or protocol, one may use the results of the geneexpression analysis or protocol to determine whether a specifictherapeutic regimen should be performed.

The word “label” when used herein refers to a compound or compositionwhich is conjugated or fused directly or indirectly to a reagent such asa nucleic acid probe or an antibody and facilitates detection of thereagent to which it is conjugated or fused. The label may itself bedetectable (e.g., radioisotope labels or fluorescent labels) or, in thecase of an enzymatic label, may catalyze chemical alteration of asubstrate compound or composition which is detectable.

General Illustrative Techniques

A sample comprising a target molecule can be obtained by methods wellknown in the art, and that are appropriate for the particular type andlocation of the disease of interest. Tissue biopsy is often used toobtain a representative piece of disease tissue. Alternatively, cellscan be obtained indirectly in the form of tissues/fluids that are knownor thought to contain the disease cells of interest. For instance,samples of disease lesions may be obtained by resection, bronchoscopy,fine needle aspiration, bronchial brushings, or from sputum, pleuralfluid or blood. Genes or gene products can be detected from diseasetissue or from other body samples such as urine, sputum or serum. Thesame techniques discussed above for detection of target genes or geneproducts in disease samples can be applied to other body samples.Disease cells are sloughed off from disease lesions and appear in suchbody samples. By screening such body samples, a simple early diagnosiscan be achieved for these diseases. In addition, the progress of therapycan be monitored more easily by testing such body samples for targetgenes or gene products.

In one embodiment, methods of the invention are useful for detecting anyautoimmune disorder with which abnormal activation (e.g.,overexpression) of interferons, in particular Type 1 interferons and/ortheir associated signaling pathway, is associated. The diagnosticmethods of the present invention are useful for clinicians so that theycan decide upon an appropriate course of treatment. For example, asample from a subject displaying a high level of expression of the genesor gene products disclosed herein might suggest a more aggressivetherapeutic regimen than a sample exhibiting a comparatively lower levelof expression. Methods of the invention can be utilized in a variety ofsettings, including for example in aiding in patient selection duringthe course of drug development, prediction of likelihood of success whentreating an individual patient with a particular treatment regimen, inassessing disease progression, in monitoring treatment efficacy, indetermining prognosis for individual patients, in assessingpredisposition of an individual to develop a particular autoimmunedisorder (e.g., systemic lupus erythematosus, Sjogren's syndrome), indifferentiating disease staging, etc.

Means for enriching a tissue preparation for disease cells are known inthe art. For example, the tissue may be isolated from paraffin orcryostat sections. Disease cells may also be separated from normal cellsby flow cytometry or laser capture microdissection. These, as well asother techniques for separating disease from normal cells, are wellknown in the art. If the disease tissue is highly contaminated withnormal cells, detection of signature gene expression profile may be moredifficult, although techniques for minimizing contamination and/or falsepositive/negative results are known, some of which are describedhereinbelow. For example, a sample may also be assessed for the presenceof a biomarker (including a mutation) known to be associated with adisease cell of interest but not a corresponding normal cell, or viceversa.

The invention also provides a variety of compositions suitable for usein performing methods of the invention. For example, the inventionprovides arrays that can be used in such methods. In one embodiment, anarray of the invention comprises individual or collections of nucleicacid molecules useful for detecting mutations of the invention. Forinstance, an array of the invention may comprises a series of discretelyplaced individual nucleic acid oligonucleotides or sets of nucleic acidoligonucleotide combinations that are hybridizable to a samplecomprising target nucleic acids, whereby such hybridization isindicative of presence or absence of a mutation of the invention.

Several techniques are well-known in the art for attaching nucleic acidsto a solid substrate such as a glass slide. One method is to incorporatemodified bases or analogs that contain a moiety that is capable ofattachment to a solid substrate, such as an amine group, a derivative ofan amine group or another group with a positive charge, into nucleicacid molecules that are synthesized. The synthesized product is thencontacted with a solid substrate, such as a glass slide, which is coatedwith an aldehyde or another reactive group which will form a covalentlink with the reactive group that is on the amplified product and becomecovalently attached to the glass slide. Other methods, such as thoseusing amino propryl silican surface chemistry are also known in the art,as disclosed at http://www.cmt.corning.com andhttp://cmgm.stanford.edu/pbrown1.

Attachment of groups to oligonucleotides which could be later convertedto reactive groups is also possible using methods known in the art. Anyattachment to nucleotides of oligonucleotides will become part ofoligonucleotide, which could then be attached to the solid surface ofthe microarray.

Amplified nucleic acids can be further modified, such as throughcleavage into fragments or by attachment of detectable labels, prior toor following attachment to the solid substrate, as required and/orpermitted by the techniques used.

Typical Methods and Materials of the Invention

The methods and assays disclosed herein are directed to the examinationof expression of one or more biomarkers in a mammalian tissue or cellsample, wherein the determination of that expression of one or more suchbiomarkers is predictive or indicative of whether the tissue or cellsample will be sensitive to treatment based on the use of interferoninhibitors. The methods and assays include those which examineexpression of biomarkers such as one or more of those listed in Table 1,2 and/or 3.

As discussed above, there are some populations of diseased human celltypes that are associated with abnormal expression of interferons suchas the Type 1 interferons which is associated with various autoimmunedisorders. It is therefore believed that the disclosed methods andassays can provide for convenient, efficient, and potentiallycost-effective means to obtain data and information useful in assessingappropriate or effective therapies for treating patients. For example, apatient having been diagnosed with an immune related condition couldhave a biopsy performed to obtain a tissue or cell sample, and thesample could be examined by way of various in vitro assays to determinewhether the patient's cells would be sensitive to a therapeutic agentsuch as an interferon inhibitor (e.g., an anti-interferon alpha antibodyor an antibody to interferon alpha receptor).

The invention provides methods for predicting the sensitivity of amammalian tissue or cells sample (such as a cell associated with anautoimmune disorder) to an interferon inhibitor. In the methods, amammalian tissue or cell sample is obtained and examined for expressionof one or more biomarkers. The methods may be conducted in a variety ofassay formats, including assays detecting mRNA expression, enzymaticassays detecting presence of enzymatic activity, andimmunohistochemistry assays. Determination of expression of suchbiomarkers in said tissues or cells will be predictive that such tissuesor cells will be sensitive to the interferon inhibitor therapy.Applicants surprisingly found that the expression of such particularbiomarkers correlates closely with presence and/or extent of variousautoimmune disorders.

As discussed below, expression of various biomarkers in a sample can beanalyzed by a number of methodologies, many of which are known in theart and understood by the skilled artisan, including but not limited to,immunohistochemical and/or Western analysis, quantitative blood basedassays (as for example Serum ELISA) (to examine, for example, levels ofprotein expression), biochemical enzymatic activity assays, in situhybridization, Northern analysis and/or PCR analysis of mRNAs, as wellas any one of the wide variety of assays that can be performed by geneand/or tissue array analysis. Typical protocols for evaluating thestatus of genes and gene products are found, for example in Ausubel etal. eds., 1995, Current Protocols In Molecular Biology, Units 2(Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18(PCR Analysis).

The protocols below relating to detection of particular biomarkers, suchas those listed in Table 1, 2 and/or 3, in a sample are provided forillustrative purposes.

Optional methods of the invention include protocols which examine ortest for presence of IRG in a mammalian tissue or cell sample. A varietyof methods for detecting IRG can be employed and include, for example,immunohistochemical analysis, immunoprecipitation, Western blotanalysis, molecular binding assays, ELISA, ELIFA, fluorescence activatedcell sorting (FACS) and the like. For example, an optional method ofdetecting the expression of IRG in a tissue or sample comprisescontacting the sample with a IRG antibody, a IRG-reactive fragmentthereof, or a recombinant protein containing an antigen binding regionof a IRG antibody; and then detecting the binding of IRG protein in thesample.

In particular embodiments of the invention, the expression of IRGproteins in a sample is examined using immunohistochemistry and stainingprotocols. Immunohistochemical staining of tissue sections has beenshown to be a reliable method of assessing or detecting presence ofproteins in a sample. Immunohistochemistry (“IHC”) techniques utilize anantibody to probe and visualize cellular antigens in situ, generally bychromogenic or fluorescent methods.

For sample preparation, a tissue or cell sample from a mammal (typicallya human patient) may be used. Examples of samples include, but are notlimited to, tissue biopsy, blood, lung aspirate, sputum, lymph fluid,etc. The sample can be obtained by a variety of procedures known in theart including, but not limited to surgical excision, aspiration orbiopsy. The tissue may be fresh or frozen. In one embodiment, the sampleis fixed and embedded in paraffin or the like.

The tissue sample may be fixed (i.e. preserved) by conventionalmethodology (See e.g., “Manual of Histological Staining Method of theArmed Forces Institute of Pathology,” 3^(rd) edition (1960) Lee G. Luna,H T (ASCP) Editor, The Blakston Division McGraw-Hill Book Company, NewYork; The Armed Forces Institute of Pathology Advanced LaboratoryMethods in Histology and Pathology (1994) Ulreka V. Mikel, Editor, ArmedForces Institute of Pathology, American Registry of Pathology,Washington, D.C.). One of skill in the art will appreciate that thechoice of a fixative is determined by the purpose for which the sampleis to be histologically stained or otherwise analyzed. One of skill inthe art will also appreciate that the length of fixation depends uponthe size of the tissue sample and the fixative used. By way of example,neutral buffered formalin, Bouin's or paraformaldehyde, may be used tofix a sample.

Generally, the sample is first fixed and is then dehydrated through anascending series of alcohols, infiltrated and embedded with paraffin orother sectioning media so that the tissue sample may be sectioned.Alternatively, one may section the tissue and fix the sections obtained.By way of example, the tissue sample may be embedded and processed inparaffin by conventional methodology (See e.g., “Manual of HistologicalStaining Method of the Armed Forces Institute of Pathology”, supra).Examples of paraffin that may be used include, but are not limited to,Paraplast, Broloid, and Tissuemay. Once the tissue sample is embedded,the sample may be sectioned by a microtome or the like (See e.g.,“Manual of Histological Staining Method of the Armed Forces Institute ofPathology”, supra). By way of example for this procedure, sections mayrange from about three microns to about five microns in thickness. Oncesectioned, the sections may be attached to slides by several standardmethods. Examples of slide adhesives include, but are not limited to,silane, gelatin, poly-L-lysine and the like. By way of example, theparaffin embedded sections may be attached to positively charged slidesand/or slides coated with poly-L-lysine.

If paraffin has been used as the embedding material, the tissue sectionsare generally deparaffinized and rehydrated to water. The tissuesections may be deparaffinized by several conventional standardmethodologies. For example, xylenes and a gradually descending series ofalcohols may be used (See e.g., “Manual of Histological Staining Methodof the Armed Forces Institute of Pathology”, supra). Alternatively,commercially available deparaffinizing non-organic agents such asHemo-De7 (CMS, Houston, Tex.) may be used.

Optionally, subsequent to the sample preparation, a tissue section maybe analyzed using IHC. IHC may be performed in combination withadditional techniques such as morphological staining and/or fluorescencein-situ hybridization. Two general methods of IHC are available; directand indirect assays. According to the first assay, binding of antibodyto the target antigen (e.g., an IRG) is determined directly. This directassay uses a labeled reagent, such as a fluorescent tag or anenzyme-labeled primary antibody, which can be visualized without furtherantibody interaction. In a typical indirect assay, unconjugated primaryantibody binds to the antigen and then a labeled secondary antibodybinds to the primary antibody. Where the secondary antibody isconjugated to an enzymatic label, a chromogenic or fluorogenic substrateis added to provide visualization of the antigen. Signal amplificationoccurs because several secondary antibodies may react with differentepitopes on the primary antibody.

The primary and/or secondary antibody used for immunohistochemistrytypically will be labeled with a detectable moiety. Numerous labels areavailable which can be generally grouped into the following categories:

(a) Radioisotopes, such as ³⁵S, ¹⁴C, ¹²⁵I, ³H, and ¹³¹I. The antibodycan be labeled with the radioisotope using the techniques described inCurrent Protocols in Immunology, Volumes 1 and 2, Coligen et al., Ed.Wiley-Interscience, New York, N.Y., Pubs. (1991) for example andradioactivity can be measured using scintillation counting.

(b) Colloidal gold particles.

(c) Fluorescent labels including, but are not limited to, rare earthchelates (europium chelates), Texas Red, rhodamine, fluorescein, dansyl,Lissamine, umbelliferone, phycocrytherin, phycocyanin, or commerciallyavailable fluorophores such SPECTRUM ORANGE? and SPECTRUM GREEN7 and/orderivatives of any one or more of the above. The fluorescent labels canbe conjugated to the antibody using the techniques disclosed in CurrentProtocols in Immunology, supra, for example. Fluorescence can bequantified using a fluorimeter.

(d) Various enzyme-substrate labels are available and U.S. Pat. No.4,275,149 provides a review of some of these. The enzyme generallycatalyzes a chemical alteration of the chromogenic substrate that can bemeasured using various techniques. For example, the enzyme may catalyzea color change in a substrate, which can be measuredspectrophotometrically. Alternatively, the enzyme may alter thefluorescence or chemiluminescence of the substrate. Techniques forquantifying a change in fluorescence are described above. Thechemiluminescent substrate becomes electronically excited by a chemicalreaction and may then emit light which can be measured (using achemiluminometer, for example) or donates energy to a fluorescentacceptor. Examples of enzymatic labels include luciferases (e.g.,firefly luciferase and bacterial luciferase; U.S. Pat. No. 4,737,456),luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease,peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase,β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g.,glucose oxidase, galactose oxidase, and glucose-6-phosphatedehydrogenase), heterocyclic oxidases (such as uricase and xanthineoxidase), lactoperoxidase, microperoxidase, and the like. Techniques forconjugating enzymes to antibodies are described in O'Sullivan et al.,Methods for the Preparation of Enzyme-Antibody Conjugates for use inEnzyme Immunoassay, in Methods in Enzym. (ed. J. Langone & H. VanVunakis), Academic press, New York, 73:147-166 (1981).

Examples of enzyme-substrate combinations include, for example:

(i) Horseradish peroxidase (HRPO) with hydrogen peroxidase as asubstrate, wherein the hydrogen peroxidase oxidizes a dye precursor(e.g., orthophenylene diamine (OPD) or 3,3′,5,5′-tetramethyl benzidinehydrochloride (TMB));

(ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate aschromogenic substrate; and

(iii) β-D-galactosidase (β-D-Gal) with a chromogenic substrate (e.g.,p-nitrophenyl-β-D-galactosidase) or fluorogenic substrate (e.g.,4-methylumbelliferyl-β-D-galactosidase).

Numerous other enzyme-substrate combinations are available to thoseskilled in the art. For a general review of these, see U.S. Pat. Nos.4,275,149 and 4,318,980. Sometimes, the label is indirectly conjugatedwith the antibody. The skilled artisan will be aware of varioustechniques for achieving this. For example, the antibody can beconjugated with biotin and any of the four broad categories of labelsmentioned above can be conjugated with avidin, or vice versa. Biotinbinds selectively to avidin and thus, the label can be conjugated withthe antibody in this indirect manner. Alternatively, to achieve indirectconjugation of the label with the antibody, the antibody is conjugatedwith a small hapten and one of the different types of labels mentionedabove is conjugated with an anti-hapten antibody. Thus, indirectconjugation of the label with the antibody can be achieved.

Aside from the sample preparation procedures discussed above, furthertreatment of the tissue section prior to, during or following IHC may bedesired. For example, epitope retrieval methods, such as heating thetissue sample in citrate buffer may be carried out (see, e.g., Leong etal. Appl. Immunohistochem. 4(3):201 (1996)).

Following an optional blocking step, the tissue section is exposed toprimary antibody for a sufficient period of time and under suitableconditions such that the primary antibody binds to the target proteinantigen in the tissue sample. Appropriate conditions for achieving thiscan be determined by routine experimentation. The extent of binding ofantibody to the sample is determined by using any one of the detectablelabels discussed above. Preferably, the label is an enzymatic label(e.g. HRPO) which catalyzes a chemical alteration of the chromogenicsubstrate such as 3,3′-diaminobenzidine chromogen. Preferably theenzymatic label is conjugated to antibody which binds specifically tothe primary antibody (e.g. the primary antibody is rabbit polyclonalantibody and secondary antibody is goat anti-rabbit antibody).

Optionally, the antibodies employed in the IHC analysis to detectexpression of an IRG are antibodies generated to bind primarily to theIRG of interest. Optionally, the anti-IRG antibody is a monoclonalantibody. Anti-IRG antibodies are readily available in the art,including from various commercial sources, and can also be generatedusing routine skills known in the art.

Specimens thus prepared may be mounted and coverslipped. Slideevaluation is then determined, e.g. using a microscope, and stainingintensity criteria, routinely used in the art, may be employed. As oneexample, staining intensity criteria may be evaluated as follows:

TABLE A Staining Pattern Score No staining is observed in cells. 0Faint/barely perceptible staining is detected in 1+ more than 10% of thecells. Weak to moderate staining is observed in more than 2+ 10% of thecells. Moderate to strong staining is observed in more than 3+ 10% ofthe cells.

In alternative methods, the sample may be contacted with an antibodyspecific for said biomarker under conditions sufficient for anantibody-biomarker complex to form, and then detecting said complex. Thepresence of the biomarker may be detected in a number of ways, such asby Western blotting and ELISA procedures for assaying a wide variety oftissues and samples, including plasma or serum. A wide range ofimmunoassay techniques using such an assay format are available, see,e.g., U.S. Pat. Nos. 4,016,043, 4,424,279 and 4,018,653. These includeboth single-site and two-site or “sandwich” assays of thenon-competitive types, as well as in the traditional competitive bindingassays. These assays also include direct binding of a labelled antibodyto a target biomarker.

Sandwich assays are among the most useful and commonly used assays. Anumber of variations of the sandwich assay technique exist, and all areintended to be encompassed by the present invention. Briefly, in atypical forward assay, an unlabelled antibody is immobilized on a solidsubstrate, and the sample to be tested brought into contact with thebound molecule. After a suitable period of incubation, for a period oftime sufficient to allow formation of an antibody-antigen complex, asecond antibody specific to the antigen, labelled with a reportermolecule capable of producing a detectable signal is then added andincubated, allowing time sufficient for the formation of another complexof antibody-antigen-labelled antibody. Any unreacted material is washedaway, and the presence of the antigen is determined by observation of asignal produced by the reporter molecule. The results may either bequalitative, by simple observation of the visible signal, or may bequantitated by comparing with a control sample containing known amountsof biomarker.

Variations on the forward assay include a simultaneous assay, in whichboth sample and labelled antibody are added simultaneously to the boundantibody. These techniques are well known to those skilled in the art,including any minor variations as will be readily apparent. In a typicalforward sandwich assay, a first antibody having specificity for thebiomarker is either covalently or passively bound to a solid surface.The solid surface is typically glass or a polymer, the most commonlyused polymers being cellulose, polyacrylamide, nylon, polystyrene,polyvinyl chloride or polypropylene. The solid supports may be in theform of tubes, beads, discs of microplates, or any other surfacesuitable for conducting an immunoassay. The binding processes arewell-known in the art and generally consist of cross-linking covalentlybinding or physically adsorbing, the polymer-antibody complex is washedin preparation for the test sample. An aliquot of the sample to betested is then added to the solid phase complex and incubated for aperiod of time sufficient (e.g. 2-40 minutes or overnight if moreconvenient) and under suitable conditions (e.g. from room temperature to40° C. such as between 25° C. and 32° C. inclusive) to allow binding ofany subunit present in the antibody. Following the incubation period,the antibody subunit solid phase is washed and dried and incubated witha second antibody specific for a portion of the biomarker. The secondantibody is linked to a reporter molecule which is used to indicate thebinding of the second antibody to the molecular marker.

An alternative method involves immobilizing the target biomarkers in thesample and then exposing the immobilized target to specific antibodywhich may or may not be labelled with a reporter molecule. Depending onthe amount of target and the strength of the reporter molecule signal, abound target may be detectable by direct labelling with the antibody.Alternatively, a second labelled antibody, specific to the firstantibody is exposed to the target-first antibody complex to form atarget-first antibody-second antibody tertiary complex. The complex isdetected by the signal emitted by the reporter molecule. By “reportermolecule”, as used in the present specification, is meant a moleculewhich, by its chemical nature, provides an analytically identifiablesignal which allows the detection of antigen-bound antibody. The mostcommonly used reporter molecules in this type of assay are eitherenzymes, fluorophores or radionuclide containing molecules (i.e.radioisotopes) and chemiluminescent molecules.

In the case of an enzyme immunoassay, an enzyme is conjugated to thesecond antibody, generally by means of glutaraldehyde or periodate. Aswill be readily recognized, however, a wide variety of differentconjugation techniques exist, which are readily available to the skilledartisan. Commonly used enzymes include horseradish peroxidase, glucoseoxidase, -galactosidase and alkaline phosphatase, amongst others. Thesubstrates to be used with the specific enzymes are generally chosen forthe production, upon hydrolysis by the corresponding enzyme, of adetectable color change. Examples of suitable enzymes include alkalinephosphatase and peroxidase. It is also possible to employ fluorogenicsubstrates, which yield a fluorescent product rather than thechromogenic substrates noted above. In all cases, the enzyme-labelledantibody is added to the first antibody-molecular marker complex,allowed to bind, and then the excess reagent is washed away. A solutioncontaining the appropriate substrate is then added to the complex ofantibody-antigen-antibody. The substrate will react with the enzymelinked to the second antibody, giving a qualitative visual signal, whichmay be further quantitated, usually spectrophotometrically, to give anindication of the amount of biomarker which was present in the sample.Alternately, fluorescent compounds, such as fluorescein and rhodamine,may be chemically coupled to antibodies without altering their bindingcapacity. When activated by illumination with light of a particularwavelength, the fluorochrome-labelled antibody adsorbs the light energy,inducing a state to excitability in the molecule, followed by emissionof the light at a characteristic color visually detectable with a lightmicroscope. As in the EIA, the fluorescent labelled antibody is allowedto bind to the first antibody-molecular marker complex. After washingoff the unbound reagent, the remaining tertiary complex is then exposedto the light of the appropriate wavelength, the fluorescence observedindicates the presence of the molecular marker of interest.Immunofluorescence and EIA techniques are both very well established inthe art. However, other reporter molecules, such as radioisotope,chemiluminescent or bioluminescent molecules, may also be employed.

It is contemplated that the above described techniques may also beemployed to detect expression of IRG.

Methods of the invention further include protocols which examine thepresence and/or expression of mRNAs, such as IRG mRNAs, in a tissue orcell sample. Methods for the evaluation of mRNAs in cells are well knownand include, for example, hybridization assays using complementary DNAprobes (such as in situ hybridization using labeled IRG riboprobes,Northern blot and related techniques) and various nucleic acidamplification assays (such as RT-PCR using complementary primersspecific for IRG, and other amplification type detection methods, suchas, for example, branched DNA, SISBA, TMA and the like).

Tissue or cell samples from mammals can be conveniently assayed for,e.g., IRG mRNAs using Northern, dot blot or PCR analysis. For example,RT-PCR assays such as quantitative PCR assays are well known in the art.In an illustrative embodiment of the invention, a method for detectingan IRG mRNA in a biological sample comprises producing cDNA from thesample by reverse transcription using at least one primer; amplifyingthe cDNA so produced using an IRG polynucleotide as sense and antisenseprimers to amplify IRG cDNAs therein; and detecting the presence of theamplified IRG cDNA. In addition, such methods can include one or moresteps that allow one to determine the levels of IRG mRNA in a biologicalsample (e.g. by simultaneously examining the levels a comparativecontrol mRNA sequence of a “housekeeping” gene such as an actin familymember). Optionally, the sequence of the amplified IRG cDNA can bedetermined.

Material embodiments of this aspect of the invention include IRG primersand primer pairs, which allow the specific amplification of thepolynucleotides of the invention or of any specific parts thereof, andprobes that selectively or specifically hybridize to nucleic acidmolecules of the invention or to any part thereof. Probes may be labeledwith a detectable marker, such as, for example, a radioisotope,fluorescent compound, bioluminescent compound, a chemiluminescentcompound, metal chelator or enzyme. Such probes and primers can be usedto detect the presence of IRG polynucleotides in a sample and as a meansfor detecting a cell expressing IRG proteins. As will be understood bythe skilled artisan, a great many different primers and probes may beprepared based on the sequences provided in herein and used effectivelyto amplify, clone and/or determine the presence and/or levels of IRGmRNAs.

Optional methods of the invention include protocols which examine ordetect mRNAs, such as IRG mRNAs, in a tissue or cell sample bymicroarray technologies. Using nucleic acid microarrays, test andcontrol mRNA samples from test and control tissue samples are reversetranscribed and labeled to generate cDNA probes. The probes are thenhybridized to an array of nucleic acids immobilized on a solid support.The array is configured such that the sequence and position of eachmember of the array is known. For example, a selection of genes thathave potential to be expressed in certain disease states may be arrayedon a solid support. Hybridization of a labeled probe with a particulararray member indicates that the sample from which the probe was derivedexpresses that gene. Differential gene expression analysis of diseasetissue can provide valuable information. Microarray technology utilizesnucleic acid hybridization techniques and computing technology toevaluate the mRNA expression profile of thousands of genes within asingle experiment. (see, e.g., WO 01/75166 published Oct. 11, 2001;(See, for example, U.S. Pat. No. 5,700,637, U.S. Pat. No. 5,445,934, andU.S. Pat. No. 5,807,522, Lockart, Nature Biotechnology, 14:1675-1680(1996); Cheung et al., Nature Genetics 21(Suppl):15-19 (1999) for adiscussion of array fabrication). DNA microarrays are miniature arrayscontaining gene fragments that are either synthesized directly onto orspotted onto glass or other substrates. Thousands of genes are usuallyrepresented in a single array. A typical microarray experiment involvesthe following steps: 1) preparation of fluorescently labeled target fromRNA isolated from the sample, 2) hybridization of the labeled target tothe microarray, 3) washing, staining, and scanning of the array, 4)analysis of the scanned image and 5) generation of gene expressionprofiles. Currently two main types of DNA microarrays are being used:oligonucleotide (usually 25 to 70 mers) arrays and gene expressionarrays containing PCR products prepared from cDNAs. In forming an array,oligonucleotides can be either prefabricated and spotted to the surfaceor directly synthesized on to the surface (in situ).

The Affymetrix GeneChip® system is a commerically available microarraysystem which comprises arrays fabricated by direct synthesis ofoligonucleotides on a glass surface. Probe/Gene Arrays:Oligonucleotides, usually 25 mers, are directly synthesized onto a glasswafer by a combination of semiconductor-based photolithography and solidphase chemical synthesis technologies. Each array contains up to 400,000different oligos and each oligo is present in millions of copies. Sinceoligonucleotide probes are synthesized in known locations on the array,the hybridization patterns and signal intensities can be interpreted interms of gene identity and relative expression levels by the AffymetrixMicroarray Suite software. Each gene is represented on the array by aseries of different oligonucleotide probes. Each probe pair consists ofa perfect match oligonucleotide and a mismatch oligonucleotide. Theperfect match probe has a sequence exactly complimentary to theparticular gene and thus measures the expression of the gene. Themismatch probe differs from the perfect match probe by a single basesubstitution at the center base position, disturbing the binding of thetarget gene transcript. This helps to determine the background andnonspecific hybridization that contributes to the signal measured forthe perfect match oligo. The Microarray Suite software subtracts thehybridization intensities of the mismatch probes from those of theperfect match probes to determine the absolute or specific intensityvalue for each probe set. Probes are chosen based on current informationfrom Genbank and other nucleotide repositories. The sequences arebelieved to recognize unique regions of the 3′ end of the gene. AGeneChip Hybridization Oven (“rotisserie” oven) is used to carry out thehybridization of up to 64 arrays at one time. The fluidics stationperforms washing and staining of the probe arrays. It is completelyautomated and contains four modules, with each module holding one probearray. Each module is controlled independently through Microarray Suitesoftware using preprogrammed fluidics protocols. The scanner is aconfocal laser fluorescence scanner which measures fluorescenceintensity emitted by the labeled cRNA bound to the probe arrays. Thecomputer workstation with Microarray Suite software controls thefluidics station and the scanner. Microarray Suite software can controlup to eight fluidics stations using preprogrammed hybridization, wash,and stain protocols for the probe array. The software also acquires andconverts hybridization intensity data into a presence/absence call foreach gene using appropriate algorithms. Finally, the software detectschanges in gene expression between experiments by comparison analysisand formats the output into .txt files, which can be used with othersoftware programs for further data analysis.

The expression of a selected biomarker may also be assessed by examininggene deletion or gene amplification. Gene deletion or amplification maybe measured by any one of a wide variety of protocols known in the art,for example, by conventional Southern blotting, Northern blotting toquantitate the transcription of mRNA (Thomas, Proc. Natl. Acad. Sci.USA, 77:5201-5205 (1980)), dot blotting (DNA analysis), or in situhybridization (e.g., FISH), using an appropriately labeled probe,cytogenetic methods or comparative genomic hybridization (CGH) using anappropriately labeled probe. By way of example, these methods may beemployed to detect deletion or amplification of IRG genes.

Expression of a selected biomarker in a tissue or cell sample may alsobe examined by way of functional or activity-based assays. For instance,if the biomarker is an enzyme, one may conduct assays known in the artto determine or detect the presence of the given enzymatic activity inthe tissue or cell sample.

In the methods of the present invention, it is contemplated that thetissue or cell sample may also be examined for the expression ofinterferons such as Type 1 interferons, and/or activation of the Type 1interferon signaling pathway, in the sample. Examining the tissue orcell sample for expression of Type 1 interferons and/or thecorresponding receptor(s), and/or activation of the Type interferonsignaling pathway, may give further information as to whether the tissueor cell sample will be sensitive to an interferon inhibitor. By way ofexample, the IHC techniques described above may be employed to detectthe presence of one of more such molecules in the sample. It iscontemplated that in methods in which a tissue or sample is beingexamined not only for the presence of IRG, but also for the presence of,e.g., Type 1 interferon, interferon receptor(s), separate slides may beprepared from the same tissue or sample, and each slide tested with areagent specific for each specific biomarker or receptor. Alternatively,a single slide may be prepared from the tissue or cell sample, andantibodies directed to each biomarker or receptor may be used inconnection with a multi-color staining protocol to allow visualizationand detection of the respective biomarkers or receptors.

Subsequent to the determination that the tissue or cell sample expressesone or more of the biomarkers indicating the tissue or cell sample willbe sensitive to treatment with interferon inhibitors, it is contemplatedthat an effective amount of the interferon inhibitor may be administeredto the mammal to treat a disorder, such as autoimmune disorder which isafflicting the mammal. Diagnosis in mammals of the various pathologicalconditions described herein can be made by the skilled practitioner.Diagnostic techniques are available in the art which allow, e.g., forthe diagnosis or detection of autoimmune related disease in a mammal.

An interferon inhibitor can be administered in accord with knownmethods, such as intravenous administration as a bolus or by continuousinfusion over a period of time, by intramuscular, intraperitoneal,intracerobrospinal, subcutaneous, intra-articular, intrasynovial,intrathecal, oral, topical, or inhalation routes. Optionally,administration may be performed through mini-pump infusion using variouscommercially available devices.

Effective dosages and schedules for administering interferon inhibitorsmay be determined empirically, and making such determinations is withinthe skill in the art. Single or multiple dosages may be employed. Forexample, an effective dosage or amount of interferon inhibitor usedalone may range from about 1:g/kg to about 100 mg/kg of body weight ormore per day. Interspecies scaling of dosages can be performed in amanner known in the art, e.g., as disclosed in Mordenti et al.,Pharmaceut. Res., 8:1351 (1991).

When in vivo administration of interferon inhibitor is employed, normaldosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammalbody weight or more per day, preferably about 1 μg/kg/day to 10mg/kg/day, depending upon the route of administration. Guidance as toparticular dosages and methods of delivery is provided in theliterature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or5,225,212. It is anticipated that different formulations will beeffective for different treatment compounds and different disorders,that administration targeting one organ or tissue, for example, maynecessitate delivery in a manner different from that to another organ ortissue.

It is contemplated that yet additional therapies may be employed in themethods. The one or more other therapies may include but are not limitedto, administration of steroids and other standard of care regimens forthe particular autoimmune disorder in question. It is contemplated thatsuch other therapies may be employed as an agent separate from theinterferon inhibitor.

For use in the applications described or suggested above, kits orarticles of manufacture are also provided by the invention. Such kitsmay comprise a carrier means being compartmentalized to receive in closeconfinement one or more container means such as vials, tubes, and thelike, each of the container means comprising one of the separateelements to be used in the method. For example, one of the containermeans may comprise a probe that is or can be detectably labeled. Suchprobe may be an antibody or polynucleotide specific for IRG gene ormessage, respectively. Where the kit utilizes nucleic acid hybridizationto detect the target nucleic acid, the kit may also have containerscontaining nucleotide(s) for amplification of the target nucleic acidsequence and/or a container comprising a reporter-means, such as abiotin-binding protein, such as avidin or streptavidin, bound to areporter molecule, such as an enzymatic, florescent, or radioisotopelabel.

The kit of the invention will typically comprise the container describedabove and one or more other containers comprising materials desirablefrom a commercial and user standpoint, including buffers, diluents,filters, needles, syringes, and package inserts with instructions foruse. A label may be present on the container to indicate that thecomposition is used for a specific therapy or non-therapeuticapplication, and may also indicate directions for either in vivo or invitro use, such as those described above.

The kits of the invention have a number of embodiments. A typicalembodiment is a kit comprising a container, a label on said container,and a composition contained within said container; wherein thecomposition includes a primary antibody that binds to a IRG polypeptidesequence, the label on said container indicates that the composition canbe used to evaluate the presence of IRG proteins in at least one type ofmammalian cell, and instructions for using the IRG antibody forevaluating the presence of IRG proteins in at least one type ofmammalian cell. The kit can further comprise a set of instructions andmaterials for preparing a tissue sample and applying antibody and probeto the same section of a tissue sample. The kit may include both aprimary and secondary antibody, wherein the secondary antibody isconjugated to a label, e.g., an enzymatic label.

Another embodiment is a kit comprising a container, a label on saidcontainer, and a composition contained within said container; whereinthe composition includes a polynucleotide that hybridizes to acomplement of the IRG polynucleotide under stringent conditions, thelabel on said container indicates that the composition can be used toevaluate the presence of IRG in at least one type of mammalian cell, andinstructions for using the IRG polynucleotide for evaluating thepresence of IRG RNA or DNA in at least one type of mammalian cell.

Other optional components in the kit include one or more buffers (e.g.,block buffer, wash buffer, substrate buffer, etc), other reagents suchas substrate (e.g., chromogen) which is chemically altered by anenzymatic label, epitope retrieval solution, control samples (positiveand/or negative controls), control slide(s) etc.

The following are examples of the methods and compositions of theinvention. It is understood that various other embodiments may bepracticed, given the general description provided above.

EXAMPLES Example 1 Materials and Methods

Expression of IFN-alpha responsive genes (IRG's) was analyzed in datafrom blood—peripheral blood mononuclear cells (PBMC) from SLE patients(with active or inactive disease) and normal donors from the UniversityOf Minnesota (Minneapolis, Minn.).

Data was produced as follows: 92 blood samples were collected ondifferent dates from 18 patients with active SLE, 19 blood samples werecollected on different dates from 5 patients with inactive SLE, and 4blood samples were collected from 4 healthy donors. PBMC was isolatedfrom whole blood by standard Ficoll gradient centrifugation. RNA wasprepared from PBMC samples using RNA Isolation Kit from Qiagen(Valencia, Calif.) and hybridized to WHG oligonucleotide microarraychips from Agilent (Palo Alto, Calif.). Raw data was processed bystandard Agilent Feature Extraction to yield Agilent log ratio data.Normal expression of genes in response to IFN-alpha was examined byisolating PBMC from healthy donors and incubating it in culture for fourhours with 100 U/ml recombinant IFN-alpha, then taking samples of thecell culture at 4, 12, 28, and 52 hours following addition of IFN-alpha.

Microarray data was clustered hierarchically in two dimensions (samplesand probes) using the xcluster software program (pearson on log 2signal) on probes with both mean signal in the top 70% ile andcoefficient of variability in the top 70% ile. Cluster data was viewedwith the Java Treeview software program. Numerical analysis wasperformed with R (www.r-project.org/), JMP (SAS Institute, Cary, N.C.)and Excel (Microsoft, Redmond, Wash.).

Results and Analysis

Microarray clustering of all samples showed significant grouping of bothsamples and genes. Sample clustering showed grouping of a large fractionof SLE patients with active disease. Gene clustering showed severaldifferent tightly grouped gene subclusters with obvious biologicalpatterns. For instance, one subcluster was highly enriched for genesknown to be specific to B cells, another to neutrophils, another forantibodies, and another for IRG's. The IRG subcluster showed aninteresting pattern with respect to samples: normal samples all showedlow expression of IRG's, while SLE samples showed a wide range ofexpression that varied from normal-like to extremely high.

The expression profiles of probes within a tight subcluster are verysimilar but not identical, and the variation between very similarprofiles may be due in significant part to noise either from biologicalor technological sources. For instance, some genes are represented onthe microarray by more than one probe, and there are several pairs ofprobes in the IRG subcluster area that represent the same gene'sexpression. In these cases, the probes clustered near to each other,sometimes immediately adjacent. Thus it appeared that a clear patternwas present and reflected in many probes, and that utilizing the datafrom several probes in order to mitigate the interference of noise inthe data might most clearly identify the pattern. Nonetheless, the genesthat were identified could be used individually as genetic identifiersthat correlate with presence of disease.

Identification of Genes Highly Induced by Interferon Alpha

In order to identify genes whose expression is highly induced by thepresence of interferon alpha, PBMC samples from healthy donors weretreated with recombinant interferon alpha and samples of the cellcultures were subjected to Agilent WHG expression analysis as describedabove. Log ratio data from these hybridizations were analyzed by two-wayANOVA (time and treatment), and 142 probes were identified by filteringof treatment p-value<5×10⁻⁷. This set of genes is a subset of geneswhose expression is induced by interferon alpha, and it constitutes aneffective tool for identifying clusters of genes in other experimentswhose common basis for co-clustering is induction by interferon alpha.

Development of a Metric that Correlates with Disease, and Identificationof Individual Genes that May Constitute Such Metric

The pattern of transcriptional activation in IRG's was measured bycalculating a single metric proportional to the Agilent ratio levels ofthe specific subgroup of probes. For example, we describe this approachbelow with the IRG probes. The pattern (the aggregate profile of IRG's)was first defined by aligning a density plot of probes induced byinterferon alpha in PBMC samples with the cluster heatmap of SLE andcontrol samples (FIG. 1). Probes were defined as IRG's by starting fromthe two most highly correlated probes and expanding the set by addingthe next most highly correlated probe or branch of probes until the setof probes appeared to contain most of the expression signature evidentin its center but not so far that it contains a significant contributionfrom a different signature. The set is comprised of the thirty-fiveprobes listed in Table 1.

The expression data of this group was then transformed into z-scores(mean scaled to 1, base-2 log transformed, then scaled to a standarddeviation of the mean of 1), and the correlation coefficient of eachprobe's profile to the mean profile was calculated. These correlationcoefficients were used as weighting factors to weight relatively heavilythe probes that showed the strongest match to the trend of the group,and to weight relatively lightly those that apparently were moreaffected by other inputs or noise.

The factors required to scale probes to 1 were multiplied by theweighting factor, to produce a composite factor that could yield anormalized, weighted metric for a single hybridization. The normal bloodsamples' signatures were multiplied by that factor, averaged across bothprobes and samples, and this number was inverted to yield a globalscaling factor that would transform the output of the average of probesfrom a sample into a metric that would be expected to be 1 for samplesfrom healthy donors. Each normalization/weighting factor was multipliedby this factor. The result was a vector of scalar values that weremultiplied by a sample expression signature and averaged to yield theType I Interferon Response Gene Metric (IRGM), a single metric measuringthe level of IFN-alpha transcriptional response in a sample.

IRGM scores were calculated and evaluated for the set of clinicalsamples used for selection of the IRGM genes. IRGM scores weresignificantly higher for patients suffering from active SLE than healthypatients (FIG. 2).

Clinical measures of SLE disease activity and severity such as SLEDAIquantitate patient disease symptoms and may correlate with expression ofgenes that underlie the etiology of the disease. In order to investigatethis hypothesis, IRGM data on individual patients were compared to thosepatients' clinical scores and lab test results. No significantcorrelation was observed between IRGM and SLEDAI, but the titer ofanti-dsDNA antibodies in serum correlated well with IRGM in manypatients with active SLE (FIG. 3). This correlation could be the basisof either assay being a surrogate for the other. It also illustrates abiological relationship that could serve as a basis for a rationaldesign of therapy for SLE.

The IRGM test, and expression of the genes that make up such a test (asset forth in Table 1), could be useful for selecting patients that wouldbenefit from IFN-α-based treatment for autoimmune disorders (e.g., SLE)by identifying patients that have a relatively high IRGM score and thushave IFN-α signaling that could be blocked. Equivalently, it could beused to predict that certain patients would not benefit from IFN-α-basedtreatment because they do not exhibit a high IRGM score and thus are notcurrently experiencing active IFN-α signaling that could be disrupted.

The IRGM test, and expression of the genes that make up such a test (asset forth in Table 1), are useful indicators in a variety of drugdevelopment, diagnostic, prognostic and therapeutic settings asdescribed above. For example, this information could be used to checkwhether patients that have responded well to anti-IFN-α treatment hadhigh levels of expression of the signaling targets of IFN-α beforetreatment and afterwards whether the treatment abrogated thatexpression. It would be a useful gauge of the extent to which aparticular treatment affects the IFN-α signaling pathway. It might be auseful bio- or pharmacodynamic marker, measuring the profile of theeffects of treatment over time.

Other Interferons

The metric-based approach described above could be utilized in a varietyof ways in characterizing disease pathways, mechanisms of action anddrug pharmacodynamics. For example, different interferon moleculesprobably have different properties that the IRGM and/or a test made thesame way based on different microarray data and/or analyses could helpmeasure and elucidate. For instance:

1) Type I interferons all signal through the same heterodimeric receptorbut may differ in their half-life, receptor affinity, or power toinitiate signaling in a target cell. These differences in magnitudesmight be measured easily and accurately by IRGM. This sort ofmeasurement could be carried out either in a cell culture experiment orin a clinical setting. Likewise, the effect of candidate drugs or drugsused in clinical settings can be gauged using this approach.

2) Different IRGM-like tests could be constructed by microarray assaysof cultured blood samples treated with different interferons. To theextent to which the tests differ from each other, they could be appliedto clinical samples to determine the relative activities of differentinterferons and/or drugs.

Other Signatures

The method used to generate the IRGM test could also be applied to anysort of expression signature, either of a state or activity of cells orof a type of cell or cells. For instance, some SLE patients show markedupmodulation of immunoglobulin gene expression, an indicator of theproduction of antibodies by plasma cells. Microarray probes reportingexpression of these genes could collectively support the calculation ofa measurement of the overall level of plasma cell activity and antibodyproduction. In another example, there are particular transcriptionalchanges associated with active mitotic cell replication. Thesetranscriptional changes could be consolidated into a test that would beapplied to a variety of biological samples to measure how actively theyare dividing. Or in yet another example, the genes whose expression isspecific to particular types of immune cells could be categorized bywhich cell type expresses them and then for each cell type a test couldbe made. This collection of tests could then be applied to any of avariety of clinical samples (blood from SLE patients, intestinalbiopsies from Crohn's Disease patients, etc.) to determine the balanceof immune cell types.

TABLE 1 Agilent WHG probes constituting a set of IRG's for WHG analysis.Thirty five probes are listed, representing twenty nine unique genes.Refseq or Genbank accession numbers, symbols and names of genes are alsoindicated. probeid accession gene symbol gene description A_24_P343929NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2 A_24_P395966NM_030776 ZBP1 Z-D binding protein 1 A_23_P259141 NM_030776 ZBP1 Z-Dbinding protein 1 A_23_P139786 NM_003733 OASL 2′-5′-oligoadenylatesynthetase-like A_24_P316965 NM_080657 RSAD2 (CIG5) radical S-adenosylmethionine domain containing 2 A_23_P17663 NM_002462 MX1 myxovirusresistance 1 A_24_P378019 NM_001572 IRF7 interferon regulatory factor 7A_23_P64828 NM_001032409 OAS1 2′,5′-oligoadenylate synthetase 1A_24_P943205 NM_001002264 EPSTI1 epithelial stromal interaction 1A_23_P23074 NM_006417 IFI44 interferon-induced protein 44 A_23_P45871NM_006820 IFI44L interferon-induced protein 44-like A_23_P819 NM_005101G1P2 interferon, alpha-inducible protein IFI-15K A_24_P28722 NM_080657RSAD2 (CIG5) radical S-adenosyl methionine domain containing 2A_24_P917810 NM_000059 BRCA2 breast cancer 2, early onset A_23_P52266NM_001001887 IFIT1 interferon-induced protein with tetratricopeptiderepeats 1 A_23_P110196 NM_016323 HERC5 hect domain and RLD 5 A_23_P47955NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3 A_23_P35412NM_001031683 IFIT3 interferon-induced protein with tetratricopeptiderepeats 3 A_24_P557479 NM_017523 HSXIAPAF1 XIAP associated factor-1A_23_P4283 NM_017523 HSXIAPAF1 XIAP associated factor-1 A_32_P132206NM_017414 USP18 ubiquitin specific peptidase 18 A_24_P317762 NM_002346RIG-E lymphocyte antigen 6 complex, locus E A_24_P316257 NM_145270FLJ36208 hypothetical protein FLJ36208 A_23_P105794 NM_001002264 EPSTI1epithelial stromal interaction 1 A_23_P166797 NM_022147 TMEM7 28 kDinterferon responsive protein A_23_P111804 NM_022750 PARP12 poly(ADP-ribose) polymerase family, member 12 A_23_P250353 NM_001013000HERC6 hect domain and RLD 6, transcript variant 3 A_24_P334361 NM_017631SGRA12061 hypothetical protein FLJ20035 A_23_P384355 NM_207315 TYKIthymidylate kinase family LPS-inducible A_24_P30194 NM_012420 IFIT5interferon-induced protein with tetratricopeptide repeats 5 A_23_P4286NM_017523 HSXIAPAF1 XIAP associated factor-1, transcript variant 1A_32_P227059 AA977193 (no symbol) (no known gene) A_23_P142750 NM_002759EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2A_24_P161018 NM_017554 PARP14 poly (ADP-ribose) polymerase family,member 14 A_24_P335305 NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3

Example 2 Materials and Methods

Expression of IFN-alpha responsive genes (IRG's) was analyzed in datafrom white blood cells (WBC) from SLE patients and healthy donorsobtained by Gene Logic Inc. (Gaithersburg, Md.).

Data was produced as follows: 72 blood samples were collected frompatients with active SLE, 46 blood samples were collected from healthydonors. RNA was prepared from WBC samples using RNA Isolation Kit fromQiagen (Valencia, Calif.) and hybridized to HGU133 oligonucleotidemicroarray chips from Affymetrix, Inc. (Santa Clara, Calif.). Raw datawas processed by Affymetrix MAS5.0 feature extraction to yield Signaldata.

Microarray data was clustered hierarchically in two dimensions (samplesand probes) using the xcluster software program (pearson on log 2signal) on probes with both mean signal in the top 70% ile andcoefficient of variability in the top 70% ile. Cluster data was viewedwith the Java Treeview software program. Numerical analysis wasperformed with R (www.r-project.org), JMP (SAS Institute, Cary, N.C.).

Results and Analysis

Microarray clustering of all samples showed significant grouping of bothsamples and genes. Sample clustering showed grouping of a large fractionof SLE patients with active disease. Gene clustering showed severaldifferent tightly grouped gene subclusters with obvious biologicalpatterns. For instance, one subcluster was highly enriched for genesknown to be specific to B cells, another to neutrophils, another forantibodies, and another for IRG's. The IRG subcluster showed aninteresting pattern with respect to samples: normal samples all showedlow expression of IRG's, while SLE samples showed a wide range ofexpression that varied from normal-like to extremely high.

The expression profiles of probes within a tight subcluster were verysimilar but not identical, and the variation between very similarprofiles may be due in significant part to noise either from biologicalor technological sources. For instance, some genes were represented onthe microarray by more than one probe, and there were several pairs ofprobes in the IRG subcluster area that represent the same gene'sexpression. In these cases, the probes clustered near to each other,sometimes immediately adjacent. Thus it appeared that a clear patternwas present and reflected in many probes, and that utilizing the datafrom several probes in order to mitigate the interference of noise inthe data might most clearly identify the pattern. Nonetheless, the genesthat were identified could be used individually as genetic identifiersthat correlate with presence of disease.

A relatively complete set of genes whose expression is indicative of aresponse to type 1 interferons (IRG) was identified. The IRG region,identified as a tightly clustered region of the clustered datacontaining 80 microarray probes highly enriched in known IRG's, was usedas the definition of an interferon response profile by averaging theclustered data in this slice of 80 probes. The averaging was performedby taking the arithmetic mean across the 80 probes to yield a vector oflength 118 that described the average relative interferon response inthe 118 samples analyzed. The similarity of each probe in the clusterdata was then compared to this signature vector by computing theSpearman correlation rho value of each pairwise comparison. Visualinspection of these rho values for probes in their clustered ordershowed an obvious maximum at the center of the IRG cluster (FIG. 4), andit also revealed clear boundaries between the region of locally elevatedcorrelation and the adjacent regions that were less correlated and wereinfluenced much more heavily by other signals and noise. The probes inthis complete IRG region are listed in Table 2. Table 3 shows probes (insome cases, multiple probes) corresponding to a subset of novel genesfrom Table 2.

All probes in this set and their corresponding genes are useful markersfor the level of response of blood cells to type I interferons. They areinformative of the response individually or when combined in any numberand combination as previously described to create an interferonsignature metric (ISM). The measurement of their expression level forthis purpose could be accomplished effectively using any of a variety ofstandard techniques, e.g., expression microarrays (e.g. commerciallyavailable arrays such as Affymetrix HGU133), or real-time PCR (e.g.Taqman).

TABLE 2 201 microarray probes constituting a set of type-I interferonresponsive genes, their Spearman (rho) correlation to the interferonsignature, Refseq or Genbank accession number, symbol, and name. ProbeRho Accession Symbol Name 226603_at 0.9760 NM_152703 SAMD9L sterilealpha motif domain containing 9-like 230036_at 0.9754 NM_152703 SAMD9Lsterile alpha motif domain containing 9-like 226702_at 0.9747 NM_207315TYKI Thymidylate kinase family LPS-inducible 242625_at 0.9733 NM_080657RSAD2 (CIG5) radical S-adenosyl methionine domain containing 2223220_s_at 0.9725 NM_031458 PARP9 poly ADP-ribose polymerase family,member 9 213797_at 0.9679 NM_080657 RSAD2 (CIG5) radical S-adenosylmethionine domain containing 2 204747_at 0.9664 NM_001031683 IFIT3interferon-induced protein with tetratricopeptide repeats 3 203153_at0.9586 NM_001001887 IFIT1 interferon-induced protein withtetratricopeptide repeats 1 226757_at 0.9582 NM_001547 IFIT2interferon-induced protein with tetratricopeptide repeats 2 229450_at0.9572 NM_001031683 IFIT3 interferon-induced protein withtetratricopeptide repeats 3 208436_s_at 0.9568 NM_001572 IRF7 interferonregulatory factor 7 219062_s_at 0.9544 NM_017742 ZCCHC2 zinc finger,CCHC domain containing 2 224701_at 0.9531 NM_017554 PARP14 polyADP-ribose polymerase family, member 14 205483_s_at 0.9511 NM_005101G1P2 interferon, alpha-inducible protein clone IFI-15K 218943_s_at0.9495 NM_014314 DDX58 (RIG1) DEAD Asp-Glu-Ala-Asp box polypeptide 58219863_at 0.9462 NM_016323 HERC5 hect domain and RLD 5 227609_at 0.9458NM_001002264 EPSTI1 epithelial stromal interaction 1 breast 219356_s_at0.9456 NM_016410 CHMP5 chromatin modifying protein 5 203596_s_at 0.9456NM_012420 IFIT5 interferon-induced protein with tetratricopeptiderepeats 5 228152_s_at 0.9422 XM_037817 LCGE22799 FLJ31033 228531_at0.9417 NM_017654 SAMD9 sterile alpha motif domain containing 9203595_s_at 0.9406 NM_012420 IFIT5 interferon-induced protein withtetratricopeptide repeats 5 202446_s_at 0.9383 NM_021105 PLSCR2phospholipid scramblase 2 228617_at 0.9379 NM_017523 HSXIAPAF1 XIAPassociated factor-1 232222_at 0.9374 NM_017742 ZCCHC2 zinc finger, CCHCdomain containing 2 204439_at 0.9356 NM_006820 IFI44L interferon-inducedprotein 44-like 212657_s_at 0.9346 NM_000577 IL1RN interleukin 1receptor antagonist 210797_s_at 0.9341 NM_003733 OASL2′-5′-oligoadenylate synthetase-like 213294_at 0.9334 P_ADB12769 PRKRdsRNA-dependent protein kinase 211012_s_at 0.9311 NM_002675 PMLpromyelocytic leukemia 202086_at 0.9302 NM_002462 MX1 myxovirusinfluenza virus resistance 1 223502_s_at 0.9300 NM_006573 TNFSF13B tumornecrosis factor ligand superfamily, member 13b 227807_at 0.9295NM_031458 PARP9 poly ADP-ribose polymerase family, member 9 214453_s_at0.9278 NM_006417 IFI44 interferon-induced protein 44 205660_at 0.9275NM_003733 OASL 2′-5′-oligoadenylate synthetase-like 228230_at 0.9273NM_033405 PRIC285 peroxisomal proliferator-activated receptor A218400_at 0.9253 NM_006187 OAS3 2′-5′-oligoadenylate synthetase 3223501_at 0.9227 NM_006573 TNFSF13B tumor necrosis factor ligandsuperfamily, member 13b 214059_at 0.9186 NM_006417 IFI44interferon-induced protein 44 202687_s_at 0.9178 NM_003810 Apo-2L Apo-2Ligand 202863_at 0.9176 NM_003113 SP140 SP140 nuclear body protein217502_at 0.9158 NM_001547 IFIT2 interferon-induced protein withtetratricopeptide repeats 2 218085_at 0.9130 NM_016410 CHMP5 chromatinmodifying protein 5 228439_at 0.9123 NM_138456 BATF2 basic leucinezipper transcription factor, ATF-like 2 209593_s_at 0.9089 NM_014506TOR1B torsin family 1, member B torsin B 222793_at 0.9079 NM_014314DDX58 (RIG1) DEAD Asp-Glu-Ala-Asp box polypeptide 58 204994_at 0.9061NM_002463 MX2 myxovirus influenza virus resistance 2 mouse 219691_at0.9029 NM_017654 SAMD9 sterile alpha motif domain containing 9208087_s_at 0.9027 NM_030776 ZBP1 Z-D binding protein 1 202270_at 0.9008NM_002053 GBP1 guanylate binding protein 1, interferon-inducible, 67 kDa231577_s_at 0.9007 NM_002053 GBP1 guanylate binding protein 1,interferon-inducible, 67 kDa 219209_at 0.9004 NM_022168 IFIH1 interferoninduced with helicase C domain 1 200986_at 0.8978 NM_000062 SERPING1Serine/cysteine proteinase inhibitor, clade G C1 inhibitor, 1 204972_at0.8964 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa242020_s_at 0.8948 NM_030776 ZBP1 Z-D binding protein 1 209498_at 0.8933NM_001024912 CEACAM1 carcinoembryonic antigen-related cell adhesionmolecule 1 235276_at 0.8931 NM_001002264 EPSTI1 epithelial stromalinteraction 1 breast 219211_at 0.8925 NM_017414 USP18 ubiquitin specificprotease 41 239277_at 0.8897 NM_001033583 ACOT9 acyl-CoA thioesterase 9243271_at 0.8892 NM_152703 SAMD9L sterile alpha motif domain containing9-like 205098_at 0.8887 NM_001295 CCR1 chemokine C-C motif receptor 1202430_s_at 0.8859 NM_021105 PLSCR2 phospholipid scramblase 2209417_s_at 0.8837 NM_005533 IFI35 interferon-induced protein 35205552_s_at 0.8789 NM_001032409 OAS1 2′,5′-oligoadenylate synthetase 1,40/46 kDa 231769_at 0.8783 NM_018438 FBXO6 F-box protein 6 241916_at0.8782 NM_021105 PLSCR2 phospholipid scramblase 2 233425_at 0.8778NM_017742 ZCCHC2 zinc finger, CCHC domain containing 2 218543_s_at0.8762 NM_022750 PARP12 poly ADP-ribose polymerase family, member 12202307_s_at 0.8742 NM_000593 TAP1 transporter 1, ATP-binding cassette,sub-family B 204698_at 0.8735 NM_002201 ISG20 interferon stimulated gene20 kDa 202269_x_at 0.8730 NM_002053 GBP1 guanylate binding protein 1,interferon-inducible, 67 kDa 232666_at 0.8711 NM_006187 OAS32′-5′-oligoadenylate synthetase 3, 100 kDa 218986_s_at 0.8703 NM_017631SGRA12061 Hypothetical protein FLJ20035 FLJ20035 205569_at 0.8675NM_014398 LAMP3 lysosomal-associated membrane protein 3 202145_at 0.8672NM_002346 LY6E (RIGE) lymphocyte antigen 6 complex, locus E 219352_at0.8671 NM_001013000 HERC6 hect domain and RLD 6 239979_at 0.8665NM_001002264 EPSTI1 epithelial stromal interaction 1 breast 223599_at0.8664 NM_001003818 TRIMP1 tripartite motif-containing pseudogene 1230866_at 0.8656 NM_006639 CYSLTR1 cysteinyl leukotriene receptor 1216565_x_at 0.8650 XM_497663 LOC391020 similar to Interferon-inducedtransmembrane protein 3 212659_s_at 0.8635 NM_000577 IL1RN interleukin 1receptor antagonist 202869_at 0.8634 NM_001032409 OAS12′,5′-oligoadenylate synthetase 1, 40/46 kDa 223952_x_at 0.8623NM_005771 DHRS9 dehydrogenase/reductase SDR family member 9 205241_at0.8614 NM_001953 SCO2 SCO cytochrome oxidase deficient homolog 2 yeast227458_at 0.8601 NM_014143 PDL1/B7-H1 programmed cell death 1 ligand 1231747_at 0.8600 NM_006639 CYSLTR1 cysteinyl leukotriene receptor 1209969_s_at 0.8576 NM_007315 STAT1 signal transducer and activator oftranscription 1, 91 kDa 218999_at 0.8561 NM_018295 AGPR4538 hypotheticalprotein MGC5242 224009_x_at 0.8535 NM_005771 DHRS9dehydrogenase/reductase SDR family member 9 228607_at 0.8529NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa205099_s_at 0.8516 NM_001295 CCR1 chemokine C-C motif receptor 1219799_s_at 0.8479 NM_005771 DHRS9 dehydrogenase/reductase SDR familymember 9 206133_at 0.8420 NM_017523 HSXIAPAF1 XIAP associated factor-1211889_x_at 0.8386 NM_001024912 CEACAM1 carcinoembryonic antigen-relatedcell adhesion molecule 1 222154_s_at 0.8365 NM_015535 DNAPTP6 DNApolymerase-transactivated protein 6 225291_at 0.8350 NM_033109 PNPT1polyribonucleotide nucleotidyltransferase 1 202864_s_at 0.8347 NM_003113SP140 SP140 nuclear body protein 210705_s_at 0.8341 NM_033034 TRIM5tripartite motif-containing 5 223167_s_at 0.8334 NM_013396 USP25ubiquitin specific protease 25 229625_at 0.8324 NM_004120 GBP5 guanylatebinding protein 5 202837_at 0.8278 NM_006700 TRAFD1 TRAF-type zincfinger domain containing 1 216243_s_at 0.8185 NM_000577 IL1RNinterleukin 1 receptor antagonist 223849_s_at 0.8180 NM_020963 MOV10 Mov10, Moloney leukemia virus 10, homolog mouse 222498_at 0.8175 NM_022461AZI2 5-azacytidine induced 2 238581_at 0.8173 NM_004120 GBP5 guanylatebinding protein 5 217933_s_at 0.8138 NM_015907 LAP3 leucineaminopeptidase 3 219519_s_at 0.8108 NM_023068 SIGLEC1 sialoadhesin208392_x_at 0.8084 NM_004509 SP110 SP110 nuclear body protein 239988_at0.8079 NM_017912 SKKS30637 Hect domain and RLD 6 230314_at 0.8074P_ADH28842 CMLM110 chronic myclogenous leukaemia (CML) gene marker #110206576_s_at 0.8072 NM_001024912 CEACAM1 carcinoembryonic antigen-relatedcell adhesion molecule 1 227347_x_at 0.8047 NM_021170 HES4 hairy andenhancer of split 4 Drosophila 202411_at 0.8038 NM_005532 IFI27interferon, alpha-inducible protein 27 219684_at 0.7998 NM_022147 TMEM7transmembrane protein 7 205003_at 0.7974 NM_014705 DOCK4 dedicator ofcytokinesis 4 212185_x_at 0.7969 NM_005953 MT2A metallothionein 2A235256_s_at 0.7957 NM_138801 GALM galactose mutarotase aldose1-epimerase 242234_at 0.7948 NM_017523 HSXIAPAF1 XIAP associatedfactor-1 211883_x_at 0.7916 NM_001024912 CEACAM1 carcinoembryonicantigen-related cell adhesion molecule 1 206513_at 0.7891 NM_004833 AIM2absent in melanoma 2 44673_at 0.7884 NM_023068 SIGLEC1 sialoadhesin209546_s_at 0.7869 NM_003661 APOL1 apolipoprotein L, 1 204415_at 0.7838NM_002038 G1P3 interferon, alpha-inducible protein clone IFI-6-16206553_at 0.7821 NM_001032731 OAS2 2′-5′-oligoadenylate synthetase 2,69/71 kDa 206461_x_at 0.7758 NM_005946 MT2A metallothionein 2A 226169_at0.7746 NM_030962 SBF2 SET binding factor 2 244398_x_at 0.7742 NM_152373ZNF684 zinc finger protein 684 238439_at 0.7659 NM_144590 ANKRD22ankyrin repeat domain 22 227649_s_at 0.7646 NM_015326 SRGAP2 SLIT-ROBORho GTPase activating protein 2 220998_s_at 0.7644 NM_030930 UNC93B1unc-93 homolog B1 C. elegans 204211_x_at 0.7628 NM_002759 EIF2AK2eukaryotic translation initiation factor 2-alpha kinase 2 224973_at0.7612 NM_017633 FAM46A family with sequence similarity 46, member A234974_at 0.7601 NM_138801 GALM galactose mutarotase aldose 1-epimerase242898_at 0.7588 NM_002759 EIF2AK2 eukaryotic translation initiationfactor 2-alpha kinase 2 232034_at 0.7581 BC080605 LOC203274 hypotheticalprotein LOC203274 231455_at 0.7560 NM_001001695 FLJ42418 FLJ42418208581_x_at 0.7546 NM_005952 MT1X metallothionein 1X 224225_s_at 0.7545NM_016135 ETV7 ets variant gene 7 (TEL2 oncogene) 205875_s_at 0.7543NM_016381 TREX1 three prime repair exonuclease 1 209286_at 0.7522NM_006449 CDC42EP3 CDC42 effector protein Rho GTPase binding 3 205715_at0.7472 NM_004334 BST1 bone marrow stromal cell antigen 1 223834_at0.7465 NM_014143 PDL1/B7-H1 programmed cell death 1 ligand 1 212285_s_at0.7414 NM_198576 AGRN agrin 230695_s_at 0.7381 NM_152732 C6orf206chromosome 6 open reading 206 219364_at 0.7381 NM_024119 LGP2 likelyortholog of mouse D11lgp2 238455_at 0.7371 NM_032812 PLXDC2 Plexindomain containing 2 201641_at 0.7343 NM_004335 BST2 Bone marrow stromalantigen 2 219439_at 0.7273 NM_020156 C1GALT1 core 1 synthase,glyc-N-acetylgal 3-beta-galtransferase, 1 224503_s_at 0.7231 NM_017742ZCCHC2 zinc finger, CCHC domain containing 2 234942_s_at 0.7226NM_052951 DNTTIP1 deoxynucleotidyltransferase, terminal, interactingprotein 1 214933_at 0.7212 NM_000068 CAC1A calcium channel,voltage-dependent, P/Q type, alpha 1A 219055_at 0.7189 NM_018079 SRBD1S1 RNA binding domain 1 225447_at 0.7179 NM_000408 GPD2glycerol-3-phosphate dehydrogenase 2 mitochondrial 236285_at 0.7173P_AAF17573 SYN22A2 Breast cancer associated SYN22A2 coding sequence217165_x_at 0.7168 NM_005946 MT2A metallothionein 2A 200923_at 0.7164NM_005567 LGALS3BP lectin, galactoside-binding, soluble, 3 bindingprotein 220104_at 0.7159 NM_020119 ZC3HAV1 zinc finger CCCH-type,antiviral 1 216950_s_at 0.7133 NM_000566 FCGR1A Fc fragment of IgG, highaffinity Ia, receptor CD64 227905_s_at 0.7115 NM_022461 AZI25-azacytidine induced 2 230997_at 0.7109 NM_145755 TTC21Atetratricopeptide repeat domain 21A 210889_s_at 0.7099 NM_001002273FCGR2B Low affinity immunoglobulin gamma fc receptor ii-b 214511_x_at0.7050 NM_000566 FCGR1A Fc fragment of IgG, high affinity Ia, receptor(CD64) 211456_x_at 0.7045 NM_001039954 MT1P2 metallothionein 1pseudogene 2 232563_at 0.7017 NM_152373 ZNF684 zinc finger protein 684235456_at 0.6926 NM_021063 HIST1H2BD histone 1, H2bd 229194_at 0.6917NM_032373 PCGF5 polycomb group ring finger 5 235157_at 0.6859 NM_017554PARP14 poly ADP-ribose polymerase family, member 14 230333_at 0.6851NM_002970 SAT Spermidine/spermine N1-acetyltransferase 231956_at 0.6813NM_020954 KIAA1618 KIAA1618 235175_at 0.6803 NM_052941 GBP4 guanylatebinding protein 4 232149_s_at 0.6777 NM_003580 NSMAF neutralsphingomyelinase N-SMase activation assoc factor 235331_x_at 0.6769NM_032373 PCGF5 polycomb group ring finger 5 221653_x_at 0.6762NM_030882 APOL2 apolipoprotein L, 2 219716_at 0.6689 NM_030641 APOL6apolipoprotein L, 6 214909_s_at 0.6669 NM_013974 DDAH2 dimethylargininedimethylaminohydrolase 2 207500_at 0.6654 NM_004347 CASP5 caspase 5,apoptosis-related cysteine protease 232081_at 0.6648 NM_004915 ABCG1ATP-binding cassette, sub-family G WHITE, member 1 241812_at 0.6584NM_015535 DNAPTP6 DNA polymerase-transactivated protein 6 230166_at0.6571 NM_133465 KIAA1958 KIAA1958 239143_x_at 0.6554 NM_016271 RNF138ring finger protein 138 217823_s_at 0.6543 NM_016021 UBE2J1ubiquitin-conjugating enzyme E2, J1 UBC6 homolog, yeast 242109_at 0.6501NM_006519 TCTEL1 t-complex-associated-testis-expressed 1-like 1206175_x_at 0.6420 NM_013360 ZNF230 zinc finger protein 230 215537_x_at0.6366 NM_013974 DDAH2 dimethylarginine dimethylaminohydrolase 2220252_x_at 0.6318 NM_025159 CXorf21 chromosome X open reading frame 21227268_at 0.6213 NM_016125 PLFL4625 PTD016 protein 216336_x_at 0.6153NM_153341 IBRDC3 IBR domain containing 3 229804_x_at 0.6077 NM_018491CBWD1 COBW domain containing 1 236013_at 0.6011 NM_000721 CAC1E calciumchannel, voltage-dependent, alpha 1E subunit 227004_at 0.5968 NM_003159CDKL5 cyclin-dependent kinase-like 5 226099_at 0.5788 NM_012081 ELL2elongation factor, R polymerase II, 2 227947_at 0.5761 NM_014721 PHACTR2phosphatase and actin regulator 2 210985_s_at 0.5722 NM_003113 SP140SP140 nuclear body protein 204326_x_at 0.5699 NM_005952 MT1Xmetallothionein 1X 233264_at 0.5515 AK022088 FLJ12026 HEMBB1001816212859_x_at 0.5285 NM_005953 MT1X metallothionein 1X 235348_at 0.5251NM_032859 C13orf6 chromosome 13 open reading frame 6 225872_at 0.5053NM_025181 SLC35F5 solute carrier family 35, member F5 235681_at 0.4913NM_021063 HIST1H2BD histone 1, H2bd 207291_at 0.4851 NM_024081 PRRG4proline rich Gla G-carboxyglutamic acid 4 transmembrane 234997_x_at0.4617 CD684982 EST1502 human spermidine/spermine N1 acetyl transferase

TABLE 3 Selected subset of novel probesets/genes from Table 2. Whereappropriate, multiple probesets (with their respective rho values) arelisted with their respective corresponding gene. Probe Rho AccessionSymbol Name 228152_s_at 0.9422 XM_037817 LCGE22799 FLJ31033 202446_s_at;202430_s_at; 0.9383; 0.8859; NM_021105 PLSCR2 phospholipid scramblase 2241916_at 0.8782 213294_at 0.9334 P_ADB12769 PRKR dsRNA-dependentprotein kinase 211012_s_at 0.9311 NM_002675 PML promyelocytic leukemia228230_at 0.9273 NM_033405 PRIC285 peroxisomal proliferator-activatedreceptor A 202687_s_at 0.9178 NM_003810 Apo-2L Apo-2 Ligand 202863_at;202864_s_at; 0.9176; 0.8347; NM_003113 SP140 SP140 nuclear body protein210985_s_at 0.5722 209498_at; 211889_x_at; 0.8933; 0.8386; NM_001024912CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1206576_s_at; 211883_x_at 0.8072; 0.7916 239277_at 0.8897 NM_001033583ACOT9 acyl-CoA thioesterase 9 231769_at 0.8783 NM_018438 FBXO6 F-boxprotein 6 202307_s_at 0.8742 NM_000593 TAP1 transporter 1, ATP-bindingcassette, sub-family B 204698_at 0.8735 NM_002201 ISG20 interferonstimulated gene 20 kDa 218986_s_at 0.8703 NM_017631 SGRA12061Hypothetical protein FLJ20035 FLJ20035 205569_at 0.8675 NM_014398 LAMP3lysosomal-associated membrane protein 3 223599_at 0.8664 NM_001003818TRIMP1 tripartite motif-containing pseudogene 1 230866_at; 231747_at0.8656; 0.8600 NM_006639 CYSLTR1 cysteinyl leukotriene receptor 1216565_x_at 0.8650 XM_497663 LOC391020 similar to Interferon-inducedtransmembrane protein 3 223952_x_at; 224009_x_at; 0.8623; 0.8535;NM_005771 DHRS9 dehydrogenase/reductase SDR family member 9 219799_s_at0.8479 205241_at 0.8614 NM_001953 SCO2 SCO cytochrome oxidase deficienthomolog 2 yeast 227458_at; 223834_at 0.8601; 0.7465 NM_014143 PDL1/B7-H1programmed cell death 1 ligand 1 209969_s_at 0.8576 NM_007315 STAT1signal transducer and activator of transcription 1, 91 kDa 218999_at0.8561 NM_018295 AGPR4538 hypothetical protein MGC5242 210705_s_at0.8341 NM_033034 TRIM5 tripartite motif-containing 5 223167_s_at 0.8334NM_013396 USP25 ubiquitin specific protease 25 229625_at; 238581_at0.8324; 0.8173 NM_004120 GBP5 guanylate binding protein 5 202837_at0.8278 NM_006700 TRAFD1 TRAF-type zinc finger domain containing 1223849_s_at 0.8180 NM_020963 MOV10 Mov10, Moloney leukemia virus 10,homolog mouse 222498_at; 227905_s_at 0.8175; 0.7115 NM_022461 AZI25-azacytidine induced 2 217933_s_at 0.8138 NM_015907 LAP3 leucineaminopeptidase 3 219519_s_at; 44673_at 0.8108; 0.7884 NM_023068 SIGLEC1sialoadhesin 208392_x_at 0.8084 NM_004509 SP110 SP110 nuclear bodyprotein 239988_at 0.8079 NM_017912 SKKS30637 Hect domain and RLD 6230314 _at 0.8074 P_ADH28842 CMLM110 chronic myclogenous leukaemia (CML)gene marker #110 227347_x_at 0.8047 NM_021170 HES4 hairy and enhancer ofsplit 4 Drosophila 202411_at 0.8038 NM_005532 IFI27 interferon,alpha-inducible protein 27 205003_at 0.7974 NM_014705 DOCK4 dedicator ofcytokinesis 4 212185_x_at; 206461_x_at; 0.7969; 0.7758; NM_005953 MT2Ametallothionein 2A 217165_x_at 0.7168 235256_s_at; 234974_at 0.7957;0.7601 NM_138801 GALM galactose mutarotase aldose 1-epimerase 206513_at0.7891 NM_004833 AIM2 absent in melanoma 2 209546_s_at 0.7869 NM_003661APOL1 apolipoprotein L, 1 204415_at 0.7838 NM_002038 G1P3 interferon,alpha-inducible protein clone IFI-6-16 206553_at 0.7821 NM_001032731OAS2 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 226169_at 0.7746NM_030962 SBF2 SET binding factor 2 244398_x_at; 232563_at 0.7742;0.7017 NM_152373 ZNF684 zinc finger protein 684 238439_at 0.7659NM_144590 ANKRD22 ankyrin repeat domain 22 227649_s_at 0.7646 NM_015326SRGAP2 SLIT-ROBO Rho GTPase activating protein 2 220998_s_at 0.7644NM_030930 UNC93B1 unc-93 homolog B1 C. elegans 224973_at 0.7612NM_017633 FAM46A family with sequence similarity 46, member A 232034_at0.7581 LOC203274 231455_at 0.7560 NM_001001695 FLJ42418 FLJ42418208581_x_at; 204326_x_at; 0.7546; 0.5699; NM_005952 MT1X metallothionein1X 212859_x_at 0.5285 224225_s_at 0.7545 NM_016135 ETV7 ets variant gene7 (TEL2 oncogene) 205875_s_at 0.7543 NM_016381 TREX1 three prime repairexonuclease 1 209286_at 0.7522 NM_006449 CDC42EP3 CDC42 effector proteinRho GTPase binding 3 205715_at 0.7472 NM_004334 BST1 bone marrow stromalcell antigen 1 212285_s_at 0.7414 NM_198576 AGRN agrin 230695_s_at0.7381 NM_152732 C6orf206 chromosome 6 open reading 206 219364_at 0.7381NM_024119 LGP2 likely ortholog of mouse D11lgp2 238455_at 0.7371NM_032812 PLXDC2 Plexin domain containing 2 201641_at 0.7343 NM_004335BST2 Bone marrow stromal antigen 2 219439_at 0.7273 NM_020156 C1GALT1core 1 synthase, glyc-N-acetylgal 3-beta-galtransferase, 1 234942_s_at0.7226 NM_052951 DNTTIP1 deoxynucleotidyltransferase, terminal,interacting protein 1 214933_at 0.7212 NM_000068 CAC1A calcium channel,voltage-dependent, P/Q type, alpha 1A 219055_at 0.7189 NM_018079 SRBD1S1 RNA binding domain 1 225447_at 0.7179 NM_000408 GPD2glycerol-3-phosphate dehydrogenase 2 mitochondrial 236285_at 0.7173P_AAF17573 SYN22A2 Breast cancer associated SYN22A2 coding sequence200923_at 0.7164 NM_005567 LGALS3BP lectin, galactoside-binding,soluble, 3 binding protein 220104_at 0.7159 NM_020119 ZC3HAV1 zincfinger CCCH-type, antiviral 1 216950_s_at; 214511_x_at 0.7133; 0.7050NM_000566 FCGR1A Fc fragment of IgG, high affinity Ia, receptor CD64230997_at 0.7109 NM_145755 TTC21A tetratricopeptide repeat domain 21A210889_s_at 0.7099 NM_001002273 FCGR2B Low affinity immunoglobulin gammafc receptor ii-b 211456_x_at 0.7045 NM_001039954 MT1P2 metallothionein 1pseudogene 2 235456_at; 235681_at 0.6926; 0.4913 NM_021063 HIST1H2BDhistone 1, H2bd 229194_at; 235331_x_at 0.6917; 0.6769 NM_032373 PCGF5polycomb group ring finger 5 230333_at 0.6851 NM_002970 SATSpermidine/spermine N1-acetyltransferase 231956_at 0.6813 NM_020954KIAA1618 KIAA1618 235175_at 0.6803 NM_052941 GBP4 guanylate bindingprotein 4 232149_s_at 0.6777 NM_003580 NSMAF neutral sphingomyelinaseN-SMase activation assoc factor 221653_x_at 0.6762 NM_030882 APOL2apolipoprotein L, 2 219716_at 0.6689 NM_030641 APOL6 apolipoprotein L, 6214909_s_at; 215537_x_at 0.6669; 0.6366 NM_013974 DDAH2 dimethylargininedimethylaminohydrolase 2 207500_at 0.6654 NM_004347 CASP5 caspase 5,apoptosis-related cysteine protease 232081_at 0.6648 NM_004915 ABCG1ATP-binding cassette, sub-family G WHITE, member 1 230166_at 0.6571NM_133465 KIAA1958 KIAA1958 239143_x_at 0.6554 NM_016271 RNF138 ringfinger protein 138 217823_s_at 0.6543 NM_016021 UBE2J1ubiquitin-conjugating enzyme E2, J1 UBC6 homolog, yeast 242109_at 0.6501NM_006519 TCTEL1 t-complex-associated-testis-expressed 1-like 1206175_x_at 0.6420 NM_013360 ZNF230 zinc finger protein 230 220252_x_at0.6318 NM_025159 CXorf21 chromosome X open reading frame 21 227268_at0.6213 NM_016125 PLFL4625 PTD016 protein 216336_x_at 0.6153 NM_153341IBRDC3 IBR domain containing 3 229804_x_at 0.6077 NM_018491 CBWD1 COBWdomain containing 1 236013_at 0.6011 NM_000721 CAC1E calcium channel,voltage-dependent, alpha 1E subunit 227004_at 0.5968 NM_003159 CDKL5cyclin-dependent kinase-like 5 226099_at 0.5788 NM_012081 ELL2elongation factor, R polymerase II, 2 227947_at 0.5761 NM_014721 PHACTR2phosphatase and actin regulator 2 233264_at 0.5515 AK022088 FLJ12026HEMBB1001816 235348_at 0.5251 NM_032859 C13orf6 chromosome 13 openreading frame 6 225872_at 0.5053 NM_025181 SLC35F5 solute carrier family35, member F5 207291_at 0.4851 NM_024081 PRRG4 proline rich GlaG-carboxyglutamic acid 4 transmembrane 234997_x_at 0.4617 CD684982EST1502 human spermidine/spermine N1 acetyl transferase

Example 3

To further assess the extent to which gene combinations comprising oneor more of the genes that have been identified herein correlate with aninterferon response gene signature, the Pearson correlation of allpossible three-gene combinations of 24 selected genes (Table 4A) wereassessed. Data are shown in Table 4B.

Materials and Methods

PA×gene tubes from Qiagen/PreAnalytix (Valencia, Calif.) were used tocollect whole blood from 35 SLE samples and 10 healthy donors. RNA wasprepared by using a blood RNA isolation kit from Qiagen/PreAnalytix(Valencia, Calif.) and the expression of twenty-four interferon-alpha(IFN α) responsive genes was assayed using routine methods, e.g., byusing primers/probes with TaqMan reagents from ABI (Foster City,Calif.). Relative abundance was determined by normalizing expression toRPL19. One “healthy” donor sample was removed from the analysis due toabnormally high expression of IFN responsive genes probably due to arecent viral infection. An Interferon Signature Metric (ISM) score wasdefined in the following manner:

-   -   1. The average expression for each gene was calculated in the        normal samples (“average normal expression”).    -   2. Ratio of expression relative to the average normal expression        (step #1) was tabulated.    -   3. The ISM score is defined for each sample using a set of        genes. The ISM score was the average of the expression ratios        (step #2) for the set of genes in the given sample.

From the 24 IFNα responsive genes, it was possible to generate 2024unique three-gene subsets. For each of the possible 2024 three-genecombination, Pearson correlations between three-gene ISM score and thetwenty four-gene ISM score were calculated. All numerical analysis wasperformed using R (http://www [insert period] r-project [insert period]org/).

Result and Analysis

While most healthy donor samples had an ISM score near one, asignificant fraction of SLE patients had considerably higher ISM scores.Further, all three-gene combination ISM scores served as high qualitysurrogates for the twenty four-gene ISM score. The histogram for thethree-gene ISM score correlation with the twenty four-gene ISM score isshown in FIG. 5. The lowest Pearson correlation was 0.73 and 70% of thecorrelations were greater than 0.95.

As evident from Table 4B, all combinations showed significantcorrelation values, with the lowest value being about 0.73. Thisdemonstrated the usefulness and flexibility of the genes disclosedhereinabove as markers of disease. Most, but not all, of the 24 selectedgenes are from Tables 1, 2 and/or 3. The high correlation observed, evenfor combinations comprising a gene(s) that is not listed in Tables 1, 2and/or 3, further confirmed the usefulness and broad applicability ofthe genes disclosed hereinabove as disease markers.

TABLE 4A List of selected 24 genes, with corresponding RefSeq ID. EPSTI1NM_001002264 RIG 1 (DDX58) NM_014314 OAS3 NM_006187 HERC5 NM_016323PARP9 NM_031458 SAMD9L NM_152703 TYKI NM_207315 CHMP5 NM_016410 ZBP1NM_030776 CIG5 (RSAD2) NM_080657 IFI44 NM_006417 IFI44L NM_006820 IFIT1NM_001548 IFIT4 (IFIT3) NM_001549 IFIT5 NM_012420 IRF7 NM_004029 G1P2NM_005101 MX1 NM_002462 OAS1 NM_002534 OAS2 NM_002535 OASL NM_003733SP110 NM_004509 RIGE (LY6E) NM_002346 XIAP NM_001167

TABLE 4B All possible 3-gene combinations of a selected group of 24genes, indicated with their respective Pearson correlation values. Gene1Gene2 Gene3 Pearson Correlation IFIT4 OAS1 MX1 0.996514 OASL CHMP5 ZBP10.996478 IFI44L OASL CIG5 0.996391 IFI44L CIG5 ZBP1 0.995869 EPSTI1 TYKIMX1 0.995702 IFIT4 HERC5 TYKI 0.995611 IFIT4 TYKI XIAP 0.995609 IFI44LOASL ZBP1 0.995602 IFI44L IFIT4 OASL 0.995504 IFIT4 OAS1 IFIT1 0.995422EPSTI1 HERC5 TYKI 0.995392 IFI44L EPSTI1 OASL 0.995385 IFI44L EPSTI1OAS3 0.995345 EPSTI1 TYKI IFIT1 0.99515 G1P2 SAMD9L SP110 0.99489 IRF7HERC5 TYKI 0.994867 IFIT5 CIG5 ZBP1 0.994863 IFI44L EPSTI1 ZBP1 0.994776IFI44L SP110 ZBP1 0.994649 RIG1 IRF7 HERC5 0.994588 TYKI IFIT1 XIAP0.994564 IFIT4 TYKI MX1 0.994522 OASL IFI44 ZBP1 0.994503 EPSTI1 G1P2SAMD9L 0.994402 IRF7 SAMD9L MX1 0.99428 IFI44L OAS2 OASL 0.994232 IFI44LCIG5 SP110 0.994183 TYKI MX1 XIAP 0.994176 IFI44L OASL IRF7 0.994168IFIT5 IFIT4 OAS3 0.994107 IRF7 HERC5 SAMD9L 0.994056 OASL CIG5 CHMP50.994043 IRF7 TYKI IFIT1 0.993998 TYKI IFIT1 SP110 0.993932 IFIT4 TYKIIFIT1 0.993875 CIG5 HERC5 TYKI 0.993865 IFIT5 IFIT4 ZBP1 0.993786 OAS2OASL CHMP5 0.993676 IFI44L IFIT4 RIGE 0.993594 EPSTI1 OAS3 CHMP50.993546 IFI44L IFIT4 OAS3 0.993513 EPSTI1 G1P2 TYKI 0.993511 EPSTI1G1P2 HERC5 0.99349 OAS1 IRF7 IFIT1 0.99348 IRF7 TYKI MX1 0.993472 IFIT5OAS2 ZBP1 0.993459 IRF7 HERC5 IFIT1 0.99345 IFI44L OASL XIAP 0.993443OAS1 CIG5 IFIT1 0.993431 IFIT4 IRF7 TYKI 0.993429 HERC5 TYKI SP1100.993356 IFIT4 RIG1 TYKI 0.993297 OAS1 IRF7 MX1 0.993259 IFIT5 IRF7 ZBP10.993164 IFIT4 G1P2 OAS1 0.993068 G1P2 IRF7 HERC5 0.992975 IFI44L OAS2CIG5 0.992931 CIG5 SAMD9L TYKI 0.992894 IRF7 HERC5 MX1 0.99289 OAS2 OASLIFI44 0.992876 HERC5 TYKI XIAP 0.992863 OASL CIG5 IFI44 0.992852 CIG5IFI44 ZBP1 0.992827 IFIT5 OAS2 IRF7 0.992666 IFI44L IRF7 CIG5 0.992636TYKI MX1 SP110 0.992558 IFI44L OASL MX1 0.992556 OAS1 CIG5 MX1 0.992546EPSTI1 IFI44 OAS3 0.992546 G1P2 CIG5 SAMD9L 0.992522 EPSTI1 RIG1 TYKI0.99252 OASL SAMD9L IFIT1 0.992509 IFIT5 EPSTI1 ZBP1 0.992466 IFI44LHERC5 RIGE 0.992413 CIG5 TYKI IFIT1 0.992392 IFI44L IRF7 ZBP1 0.992374G1P2 IRF7 SAMD9L 0.992327 IFIT4 SAMD9L TYKI 0.992311 IFI44L OASL SP1100.992307 IFIT5 OAS2 CIG5 0.992229 IFI44L IFIT1 RIGE 0.992209 IFI44LIFIT4 ZBP1 0.992195 IFI44L CIG5 XIAP 0.992193 IFIT5 EPSTI1 OAS3 0.99217IFI44L OAS2 EPSTI1 0.992154 IFI44L EPSTI1 CIG5 0.992137 IFI44L OAS2SP110 0.99207 EPSTI1 SAMD9L TYKI 0.99207 IFI44L MX1 RIGE 0.992058 OASLCHMP5 XIAP 0.992049 G1P2 HERC5 XIAP 0.992014 IFI44L OASL IFIT1 0.992005G1P2 SAMD9L ZBP1 0.991994 IFI44L EPSTI1 RIGE 0.991991 IFIT5 OAS2 MX10.991941 IRF7 SAMD9L IFIT1 0.991891 IFI44L IRF7 OAS3 0.991715 IFIT4EPSTI1 TYKI 0.991674 EPSTI1 G1P2 OAS1 0.991603 IFI44L OAS2 ZBP1 0.991594EPSTI1 OAS1 MX1 0.991562 CIG5 HERC5 SAMD9L 0.99156 IFIT5 OAS3 IFIT10.991555 IFIT5 OASL MX1 0.991528 OAS1 IFIT1 MX1 0.991486 IFIT4 G1P2SAMD9L 0.991439 IFIT5 CIG5 XIAP 0.991397 OAS2 IFI44 ZBP1 0.991331 EPSTI1OASL CHMP5 0.991303 HERC5 IFIT1 XIAP 0.991268 G1P2 HERC5 SP110 0.99125CIG5 TYKI MX1 0.991247 OASL SAMD9L MX1 0.991199 IFIT5 IFIT4 OAS20.991186 IFIT5 IRF7 OAS3 0.991178 IFI44L OAS2 IRF7 0.991172 IFIT5 IFIT4OASL 0.991098 IFIT5 IRF7 CIG5 0.991095 IFI44L OASL HERC5 0.991094 IFI44LRIGE XIAP 0.99101 OASL IRF7 CHMP5 0.990968 IFIT4 SAMD9L MX1 0.990947IFIT5 OAS3 MX1 0.990942 IFIT4 G1P2 HERC5 0.990937 G1P2 OAS1 CIG50.990933 G1P2 IFIT1 XIAP 0.990886 SAMD9L MX1 XIAP 0.990878 OAS3 CHMP5SP110 0.990877 G1P2 TYKI SP110 0.990867 EPSTI1 OAS1 IFIT1 0.990838 G1P2OASL SAMD9L 0.990826 IFI44L CIG5 RIGE 0.990812 SAMD9L TYKI SP1100.990776 IFIT5 CIG5 MX1 0.990775 CHMP5 RIGE XIAP 0.990758 OASL TYKIIFIT1 0.990748 HERC5 MX1 XIAP 0.990729 EPSTI1 G1P2 IFIT1 0.9907 IRF7OAS3 CHMP5 0.990687 EPSTI1 OASL IFI44 0.990632 G1P2 OAS1 IFIT1 0.990614IFIT5 XIAP ZBP1 0.990611 IFIT4 OAS1 HERC5 0.990512 IFIT4 HERC5 SAMD9L0.990506 EPSTI1 IFI44 ZBP1 0.990464 OASL CHMP5 SP110 0.990463 IFIT5 OASLIFIT1 0.990412 EPSTI1 TYKI XIAP 0.990325 EPSTI1 IRF7 TYKI 0.990315 G1P2SAMD9L XIAP 0.990306 IFI44L CIG5 OAS3 0.990281 IFIT5 OAS2 EPSTI10.990115 CIG5 SAMD9L MX1 0.990079 SAMD9L TYKI ZBP1 0.989993 OAS2 TYKIIFIT1 0.989986 EPSTI1 SAMD9L MX1 0.989945 IFI44 RIGE ZBP1 0.989942 IFIT5MX1 RIGE 0.989937 IFI44L OAS3 SP110 0.989929 IFIT5 MX1 ZBP1 0.98985IFI44L SAMD9L RIGE 0.989814 CIG5 IFI44 RIGE 0.989794 OAS2 CIG5 IFI440.989763 OASL HERC5 SAMD9L 0.989717 IFIT4 IRF7 SAMD9L 0.989667 IFIT5IFIT1 RIGE 0.989587 IFIT4 IRF7 HERC5 0.989574 IFIT5 OASL ZBP1 0.989563TYKI IFIT1 ZBP1 0.989561 G1P2 CIG5 HERC5 0.989534 HERC5 TYKI MX1 0.9895EPSTI1 IFI44 RIGE 0.989498 G1P2 OAS1 MX1 0.989491 IRF7 SAMD9L TYKI0.989455 CIG5 IFI44 OAS3 0.989384 IFIT5 OASL CIG5 0.989345 IFIT4 G1P2TYKI 0.989323 IFI44L OAS3 HERC5 0.989322 IFIT4 TYKI ZBP1 0.989292 IFIT5SP110 ZBP1 0.98929 IFI44 SP110 ZBP1 0.989289 IFI44L XIAP ZBP1 0.989258HERC5 TYKI IFIT1 0.989244 IFIT5 OAS2 IFIT1 0.989239 EPSTI1 G1P2 MX10.98921 G1P2 IRF7 IFIT1 0.989159 IFI44L IFIT4 OAS2 0.989146 OAS3 CHMP5XIAP 0.989141 OASL OAS3 CHMP5 0.989136 OASL IFI44 XIAP 0.989112 IFI44LEPSTI1 SP110 0.989091 IFI44L IRF7 SP110 0.989077 IFI44L IFIT4 CIG50.989073 CIG5 OAS3 CHMP5 0.989057 IFI44 RIGE XIAP 0.989037 CIG5 SAMD9LIFIT1 0.989029 IFI44L CIG5 HERC5 0.989011 IFIT5 OAS3 HERC5 0.988963IFIT4 HERC5 XIAP 0.988945 IFIT4 HERC5 MX1 0.988925 IFIT5 OAS3 XIAP0.988891 IFI44L IFIT4 SP110 0.988869 IFI44L OAS3 XIAP 0.988845 CHMP5RIGE ZBP1 0.988767 CIG5 CHMP5 RIGE 0.988756 IFI44L OAS3 IFIT1 0.988746RIG1 IRF7 SAMD9L 0.988717 IFI44 MX1 RIGE 0.988705 SAMD9L IFIT1 XIAP0.988634 EPSTI1 CHMP5 RIGE 0.988543 IFI44L CIG5 MX1 0.988509 IFIT5 MX1SP110 0.988438 HERC5 TYKI ZBP1 0.988437 OAS1 IFIT1 ZBP1 0.988433 IFIT4HERC5 IFIT1 0.988422 IRF7 TYKI XIAP 0.988382 IFIT5 IFIT1 ZBP1 0.988359IFIT5 OAS2 OASL 0.988341 IFIT5 IFIT4 CIG5 0.988316 SAMD9L IFIT1 ZBP10.988312 G1P2 IFIT1 SP110 0.988303 OAS1 IFIT1 XIAP 0.9883 OASL SAMD9LTYKI 0.988278 HERC5 CHMP5 RIGE 0.988269 IFIT4 OAS1 TYKI 0.988268 OAS2OAS1 IFIT1 0.988248 G1P2 MX1 XIAP 0.988232 OAS1 HERC5 MX1 0.988215 OAS1CIG5 HERC5 0.988211 HERC5 SAMD9L ZBP1 0.988167 OAS2 HERC5 TYKI 0.988163IFI44 OAS3 ZBP1 0.988139 CIG5 CHMP5 ZBP1 0.988136 IFI44L IRF7 RIGE0.988106 IFIT4 IFI44 OAS3 0.988101 OAS2 SAMD9L TYKI 0.988081 IFIT5 CIG5IFIT1 0.988073 IFIT5 EPSTI1 CIG5 0.988072 IFIT4 OASL IFI44 0.98801 IFI44HERC5 RIGE 0.987984 IFIT4 G1P2 XIAP 0.987951 IFI44L MX1 SP110 0.98795OAS1 MX1 XIAP 0.987945 RIG1 IRF7 IFIT1 0.987936 IFIT4 RIG1 HERC50.987933 IFIT4 SAMD9L IFIT1 0.987928 IFI44L EPSTI1 IRF7 0.987927 IFIT4OAS1 IRF7 0.987914 IFIT5 OASL XIAP 0.987913 IFIT4 IFI44 RIGE 0.987912IFIT5 CIG5 OAS3 0.987904 IFIT4 SAMD9L XIAP 0.987896 OAS2 G1P2 SAMD9L0.987775 OASL HERC5 IFIT1 0.987735 IRF7 IFI44 OAS3 0.987734 IFIT5 CIG5HERC5 0.98773 EPSTI1 HERC5 MX1 0.987723 G1P2 CIG5 TYKI 0.98772 IFIT5IFIT4 RIGE 0.987715 IFI44L RIGE ZBP1 0.987715 IFIT5 OASL IRF7 0.987699OAS1 HERC5 IFIT1 0.987696 EPSTI1 HERC5 SAMD9L 0.987685 OASL IRF7 IFI440.98768 IFI44L RIG1 OASL 0.987635 EPSTI1 RIG1 G1P2 0.987607 IFIT4 CIG5TYKI 0.987605 OAS2 EPSTI1 IFI44 0.987589 IFIT5 OAS2 XIAP 0.987588 OAS2TYKI MX1 0.987555 OASL IFI44 MX1 0.987554 CHMP5 MX1 RIGE 0.987534 IFI44LOAS3 MX1 0.987521 IFI44 OAS3 SP110 0.987441 EPSTI1 HERC5 IFIT1 0.987435G1P2 HERC5 IFIT1 0.987431 IFIT4 TYKI SP110 0.9874 OAS2 IFI44 RIGE0.987335 IRF7 HERC5 XIAP 0.987327 OAS3 CHMP5 ZBP1 0.987314 HERC5 SAMD9LXIAP 0.987305 G1P2 HERC5 SAMD9L 0.987303 OASL HERC5 TYKI 0.987292 RIG1IRF7 TYKI 0.987272 IFI44 OAS3 XIAP 0.987263 OASL TYKI MX1 0.987226SAMD9L MX1 ZBP1 0.987216 G1P2 TYKI XIAP 0.987186 RIG1 IFIT1 XIAP0.987143 CIG5 HERC5 IFIT1 0.987143 OASL CHMP5 MX1 0.987113 IFIT5 CIG5SP110 0.987103 HERC5 SAMD9L MX1 0.987078 EPSTI1 SAMD9L IFIT1 0.987021IFI44L EPSTI1 XIAP 0.986996 IFIT4 G1P2 IFIT1 0.986962 IFIT5 OAS2 SP1100.986961 TYKI IFIT1 MX1 0.986955 IFI44 IFIT1 RIGE 0.98694 G1P2 OAS1 IRF70.986929 RIG1 TYKI XIAP 0.986927 IFI44L SP110 XIAP 0.986913 IFIT5 EPSTI1OASL 0.986895 OASL IFI44 SP110 0.986847 SAMD9L MX1 SP110 0.986839 IFIT4IFIT1 XIAP 0.986801 G1P2 SAMD9L MX1 0.986792 SAMD9L TYKI MX1 0.986776IFIT1 MX1 XIAP 0.986772 RIG1 HERC5 XIAP 0.986653 IFIT4 SAMD9L ZBP10.986638 CIG5 IFI44 SP110 0.986615 RIG1 TYKI MX1 0.986584 IFI44L CIG5IFIT1 0.986574 CIG5 TYKI XIAP 0.986567 SAMD9L TYKI XIAP 0.986554 IFI44LRIG1 RIGE 0.986514 IFIT4 OASL CHMP5 0.986483 IFI44L OAS2 MX1 0.986478CIG5 IFI44 XIAP 0.98647 IFI44L G1P2 RIGE 0.986469 IRF7 IFI44 ZBP10.986437 EPSTI1 CIG5 IFI44 0.986418 RIG1 CIG5 TYKI 0.986387 RIG1 TYKIIFIT1 0.986336 IFIT5 EPSTI1 MX1 0.986313 IRF7 IFIT1 XIAP 0.986307 IFIT4MX1 XIAP 0.98627 IFIT4 OAS3 CHMP5 0.986258 G1P2 IRF7 MX1 0.986258 OAS2IFI44 SP110 0.986255 IFIT5 G1P2 CIG5 0.986247 IFI44L HERC5 SP1100.986229 G1P2 OASL IFIT1 0.986183 G1P2 SAMD9L IFIT1 0.986168 TYKI MX1ZBP1 0.986151 CHMP5 IFIT1 RIGE 0.986136 OAS1 IRF7 HERC5 0.986057 IRF7IFIT1 MX1 0.986039 IFIT5 HERC5 RIGE 0.985983 IFIT5 OAS2 HERC5 0.985946RIG1 IRF7 MX1 0.985944 IFI44 XIAP ZBP1 0.985944 IFI44L G1P2 OASL0.985941 IFIT5 OASL HERC5 0.98592 G1P2 HERC5 MX1 0.985913 OAS2 OAS1 MX10.98591 IFIT5 G1P2 ZBP1 0.985875 OAS1 CIG5 TYKI 0.985852 RIG1 G1P2 HERC50.985831 OAS1 OASL IFIT1 0.985827 G1P2 CIG5 IFIT1 0.985799 IFI44L OAS3ZBP1 0.985763 IFI44L OAS2 XIAP 0.985746 IFIT5 HERC5 ZBP1 0.985738 RIG1HERC5 MX1 0.985734 IRF7 CIG5 TYKI 0.985724 CIG5 HERC5 MX1 0.985709 IFIT4RIG1 SAMD9L 0.985702 OAS2 SAMD9L MX1 0.985696 OAS3 HERC5 CHMP5 0.985677OASL HERC5 CHMP5 0.985675 EPSTI1 G1P2 XIAP 0.985614 IFIT4 G1P2 MX10.985575 OAS2 SAMD9L IFIT1 0.985558 IFI44 OAS3 HERC5 0.985493 IFIT4 OASLTYKI 0.985491 IFIT5 OAS2 G1P2 0.985467 CHMP5 SP110 ZBP1 0.985431 RIG1MX1 XIAP 0.985418 IFI44L HERC5 ZBP1 0.985411 G1P2 HERC5 ZBP1 0.985399IFI44L MX1 ZBP1 0.985399 RIG1 HERC5 IFIT1 0.985388 OASL IFI44 IFIT10.985349 RIG1 OAS1 MX1 0.985314 IFIT4 IFI44 ZBP1 0.985306 IFIT4 OASLSAMD9L 0.985271 OASL IFI44 HERC5 0.985262 IFIT4 OAS2 TYKI 0.985259 IRF7CHMP5 RIGE 0.985241 G1P2 IRF7 TYKI 0.98524 RIG1 SAMD9L MX1 0.985203 G1P2OASL HERC5 0.985184 IFI44L IFIT4 EPSTI1 0.985167 SAMD9L IFIT1 SP1100.985161 HERC5 SAMD9L SP110 0.985136 IFI44L EPSTI1 MX1 0.985133 IFIT4CHMP5 RIGE 0.985089 IFI44L IFIT1 SP110 0.985074 OASL CHMP5 IFIT10.985052 IFI44L OAS2 RIGE 0.985038 OAS1 MX1 ZBP1 0.985036 IFIT5 G1P2SP110 0.985035 RIG1 HERC5 TYKI 0.98502 IFI44L OAS2 HERC5 0.985013 OASLIFI44 OAS3 0.984994 IFIT5 OAS3 ZBP1 0.984992 IRF7 CIG5 IFI44 0.984947EPSTI1 CHMP5 ZBP1 0.984947 IFI44L G1P2 SP110 0.984929 IFIT5 IFIT4 SP1100.984889 IFI44 OAS3 MX1 0.984882 IFIT5 IFIT4 XIAP 0.984858 G1P2 OAS1ZBP1 0.984857 IFI44L OAS2 IFIT1 0.984833 IFIT5 EPSTI1 IRF7 0.984785IFI44L IFIT1 ZBP1 0.984771 G1P2 OAS1 HERC5 0.984751 IFI44L OAS3 SAMD9L0.984637 IFIT5 EPSTI1 XIAP 0.984622 OAS2 IRF7 IFI44 0.984619 IFIT4 IRF7IFIT1 0.984565 IFIT5 IFIT1 SP110 0.984547 SAMD9L TYKI IFIT1 0.984535HERC5 SAMD9L IFIT1 0.984528 IFI44L CIG5 TYKI 0.984518 RIG1 OAS1 IFIT10.984505 IFI44L OASL SAMD9L 0.984455 IRF7 IFI44 RIGE 0.984421 IFI44LG1P2 CIG5 0.98441 OAS2 CHMP5 RIGE 0.98438 G1P2 TYKI IFIT1 0.984362 IFIT5G1P2 OASL 0.98435 SAMD9L CHMP5 RIGE 0.98435 IFIT4 OAS1 CIG5 0.984347OAS2 HERC5 SAMD9L 0.98434 IFIT4 G1P2 IRF7 0.984323 G1P2 HERC5 TYKI0.984302 IRF7 CIG5 SAMD9L 0.984261 EPSTI1 G1P2 IRF7 0.984258 OAS1 TYKIMX1 0.984212 IFI44L RIG1 CIG5 0.984189 IFI44 OAS3 IFIT1 0.984148 OAS1CIG5 SAMD9L 0.984088 IRF7 SAMD9L XIAP 0.984046 IFIT4 OAS1 XIAP 0.983986G1P2 MX1 SP110 0.983965 OAS1 TYKI IFIT1 0.983952 IFIT4 OAS1 SAMD9L0.983939 IRF7 MX1 XIAP 0.983917 G1P2 IFI44 RIGE 0.983911 EPSTI1 OAS1TYKI 0.983904 IFI44L OASL TYKI 0.983891 IFIT5 OAS2 PARP9 0.983888 RIG1G1P2 XIAP 0.983881 IFIT5 G1P2 RIGE 0.983874 OAS2 CHMP5 ZBP1 0.983861IFIT4 RIG1 OAS1 0.983828 G1P2 IFIT1 ZBP1 0.983828 IFIT4 IRF7 MX10.983803 OASL HERC5 MX1 0.983775 RIG1 CIG5 SAMD9L 0.983728 IFIT5 RIGEXIAP 0.983696 HERC5 IFIT1 SP110 0.983625 IFIT5 CIG5 PARP9 0.983607 OASLCHMP5 RIGE 0.983598 IFI44L IFIT4 XIAP 0.983588 IRF7 SAMD9L ZBP1 0.983584IFIT5 OAS3 SAMD9L 0.983578 G1P2 TYKI ZBP1 0.983567 EPSTI1 OAS1 HERC50.983564 HERC5 IFIT1 MX1 0.983432 IFIT4 EPSTI1 G1P2 0.98341 IFIT5 MX1XIAP 0.983401 SAMD9L IFIT1 MX1 0.983359 OAS3 CHMP5 MX1 0.983261 OAS2IFI44 OAS3 0.983253 IFIT4 OAS1 ZBP1 0.983249 G1P2 IRF7 XIAP 0.983205OAS3 CHMP5 IFIT1 0.983177 HERC5 IFIT1 ZBP1 0.983163 IFIT5 IFIT4 EPSTI10.983135 IFIT5 OAS3 SP110 0.983121 OAS1 IFIT1 SP110 0.983118 OAS2 CIG5CHMP5 0.983111 IFI44L OASL OAS3 0.983103 G1P2 OAS1 SP110 0.983094 G1P2OAS1 XIAP 0.983073 EPSTI1 IRF7 HERC5 0.983059 IFIT5 EPSTI1 G1P2 0.983057IFIT5 IFIT4 IRF7 0.983047 IFI44L EPSTI1 HERC5 0.982974 OAS2 G1P2 OAS10.982973 IFIT4 RIG1 G1P2 0.98284 EPSTI1 IRF7 SAMD9L 0.982832 OAS3 SAMD9LIFIT1 0.98283 G1P2 TYKI MX1 0.982823 IFIT5 IRF7 MX1 0.982823 CIG5 IFI44MX1 0.982815 IFIT5 IRF7 SP110 0.982806 EPSTI1 IFIT1 MX1 0.982804 OAS2G1P2 HERC5 0.982779 HERC5 SAMD9L TYKI 0.982773 OASL TYKI CHMP5 0.98276OAS1 SAMD9L MX1 0.982709 IFI44L TYKI RIGE 0.982691 IFI44L RIG1 OAS30.982688 IFIT4 IFIT1 MX1 0.982616 EPSTI1 CIG5 TYKI 0.982605 G1P2 CIG5MX1 0.982585 TYKI CHMP5 RIGE 0.982585 IFI44L IFIT4 IRF7 0.982564 IFIT5CIG5 TYKI 0.982489 G1P2 CHMP5 RIGE 0.98248 IFIT5 OAS3 PARP9 0.982456IFIT4 EPSTI1 OAS1 0.98245 CIG5 CHMP5 XIAP 0.982444 IRF7 CHMP5 ZBP10.982443 IFIT5 SAMD9L RIGE 0.982442 CIG5 CHMP5 SP110 0.982432 IFIT5EPSTI1 IFIT1 0.982364 IFIT5 G1P2 OAS3 0.982346 OAS2 IFI44 XIAP 0.982312CIG5 IFI44 HERC5 0.982284 OAS2 G1P2 TYKI 0.982279 RIG1 G1P2 IFIT10.982209 IFI44L EPSTI1 G1P2 0.982198 OASL IFIT1 MX1 0.982165 OAS1 OASLMX1 0.982158 IFIT4 RIG1 MX1 0.982123 IFI44L TYKI SP110 0.982105 IFIT5RIG1 ZBP1 0.982033 IFI44L SP110 RIGE 0.982032 IFI44L EPSTI1 IFIT10.982017 IFIT4 CIG5 SAMD9L 0.981999 IFIT5 IFIT4 MX1 0.981994 IFIT5 RIG1OAS3 0.981987 OAS2 IFI44 MX1 0.981967 OAS2 G1P2 IFIT1 0.981944 IFIT4OAS2 IFI44 0.981942 IFIT5 CIG5 RIGE 0.981929 RIG1 G1P2 SAMD9L 0.981924EPSTI1 TYKI ZBP1 0.981909 IFIT5 RIG1 CIG5 0.9819 IFI44L G1P2 ZBP10.981887 OAS2 HERC5 IFIT1 0.981886 G1P2 OASL IFI44 0.981878 IFI44 SAMD9LRIGE 0.981874 IFIT5 SP110 XIAP 0.981729 CIG5 PARP9 SAMD9L 0.981712 OAS3HERC5 SAMD9L 0.981703 EPSTI1 RIG1 HERC5 0.981663 IFIT5 EPSTI1 RIGE0.981653 RIG1 SAMD9L ZBP1 0.981639 HERC5 MX1 SP110 0.981627 IFIT5 IRF7XIAP 0.981625 IFIT4 RIG1 IFIT1 0.981605 IFI44 MX1 ZBP1 0.9816 RIG1 G1P2IRF7 0.98159 IFI44L CIG5 PARP9 0.981588 IRF7 TYKI ZBP1 0.981572 IFI44LOAS1 CIG5 0.981535 OAS1 MX1 SP110 0.981522 IRF7 CIG5 HERC5 0.981504 OASLIFI44 RIGE 0.98145 IFIT5 HERC5 SP110 0.981389 IFIT4 CIG5 IFI44 0.981344EPSTI1 PARP9 TYKI 0.981338 IFI44L IRF7 XIAP 0.981327 G1P2 IFIT1 MX10.981177 SAMD9L IFIT1 RIGE 0.981164 CHMP5 XIAP ZBP1 0.981034 IRF7 CIG5CHMP5 0.98102 IFI44L CIG5 SAMD9L 0.980991 G1P2 OASL TYKI 0.980952 IFIT4EPSTI1 SAMD9L 0.980931 CIG5 SAMD9L XIAP 0.98087 IFI44L RIG1 ZBP10.980847 G1P2 OASL CHMP5 0.98084 RIG1 CIG5 HERC5 0.980836 IFI44L OAS2G1P2 0.980731 IFI44L OAS2 TYKI 0.980703 IFIT5 OAS2 RIG1 0.980656 IFI44LEPSTI1 TYKI 0.980647 RIG1 TYKI SP110 0.980579 EPSTI1 IFIT1 XIAP 0.980575IFI44 SP110 RIGE 0.980565 IFI44 HERC5 ZBP1 0.980564 EPSTI1 CIG5 CHMP50.980544 EPSTI1 IFI44 XIAP 0.980516 IFIT5 OAS2 TYKI 0.980487 EPSTI1 IRF7IFIT1 0.980474 IFI44L TYKI ZBP1 0.98047 IFI44L OAS2 OAS3 0.980469 EPSTI1IFI44 SP110 0.980453 OAS1 OAS3 IFIT1 0.980399 G1P2 OASL MX1 0.980398OAS1 CHMP5 RIGE 0.980281 IFIT5 EPSTI1 HERC5 0.98028 OAS1 SAMD9L IFIT10.980165 OAS3 TYKI CHMP5 0.980145 IFIT4 EPSTI1 HERC5 0.980116 OAS2EPSTI1 CHMP5 0.980093 IFI44L OAS3 TYKI 0.980031 EPSTI1 HERC5 XIAP0.980031 RIG1 SAMD9L IFIT1 0.98002 IFI44L OAS1 RIGE 0.980003 G1P2 SAMD9LRIGE 0.979981 IFIT5 IFIT1 XIAP 0.979977 IFI44L OASL PARP9 0.979964 CHMP5SP110 RIGE 0.979922 OAS2 OAS3 CHMP5 0.979909 IFIT5 EPSTI1 SP110 0.97989RIG1 HERC5 SAMD9L 0.97989 OAS2 CHMP5 SP110 0.979884 G1P2 SAMD9L TYKI0.979881 IFIT5 OAS2 OAS3 0.979865 CIG5 IFIT1 MX1 0.97981 IFI44L G1P2OAS3 0.979733 IFIT5 TYKI ZBP1 0.97972 CIG5 IFI44 IFIT1 0.979594 OAS2IFI44 HERC5 0.979577 IFIT4 PARP9 TYKI 0.979539 OAS1 OAS3 CHMP5 0.979509IFIT5 IRF7 RIGE 0.979509 TYKI XIAP ZBP1 0.979497 EPSTI1 MX1 XIAP0.979484 CIG5 HERC5 XIAP 0.979467 IFIT5 RIGE ZBP1 0.979447 OAS3 SAMD9LCHMP5 0.979429 IFIT5 IRF7 IFIT1 0.979416 EPSTI1 IRF7 IFI44 0.979334 G1P2CIG5 IFI44 0.979329 IFIT4 G1P2 ZBP1 0.979297 IFIT4 OASL IFIT1 0.979261EPSTI1 IRF7 MX1 0.979237 IFI44 IFIT1 ZBP1 0.979214 IFI44L MX1 XIAP0.979195 HERC5 MX1 ZBP1 0.979186 IFI44L IRF7 MX1 0.979186 OAS1 PARP9IFIT1 0.979168 OAS2 IRF7 TYKI 0.979158 EPSTI1 RIG1 IFIT1 0.979136 EPSTI1RIG1 MX1 0.979132 IFI44L OAS3 PARP9 0.979131 IFI44 MX1 SP110 0.979127OAS1 IRF7 CIG5 0.979073 IFIT4 PARP9 SAMD9L 0.979062 IFIT4 HERC5 ZBP10.979058 RIG1 CHMP5 RIGE 0.979057 G1P2 CIG5 XIAP 0.979049 OAS1 HERC5ZBP1 0.979026 IFI44L OASL RIGE 0.979004 OAS2 IRF7 CHMP5 0.978997 EPSTI1RIG1 SAMD9L 0.978996 OASL IRF7 SAMD9L 0.978946 OAS2 HERC5 MX1 0.978889HERC5 SAMD9L RIGE 0.978849 IFIT4 CIG5 HERC5 0.978822 IFIT4 OASL HERC50.978804 RIG1 G1P2 MX1 0.978789 IFIT5 CIG5 SAMD9L 0.978769 IFI44L OAS1OAS3 0.978759 OAS3 SAMD9L MX1 0.978718 RIG1 TYKI ZBP1 0.978668 G1P2IFI44 ZBP1 0.978638 EPSTI1 IFI44 MX1 0.97863 OAS2 IFI44 IFIT1 0.978619CIG5 PARP9 TYKI 0.978512 EPSTI1 PARP9 SAMD9L 0.978467 EPSTI1 SAMD9L XIAP0.978424 IFIT5 OAS3 TYKI 0.978409 IFIT5 OASL SP110 0.978403 IFI44 SP110XIAP 0.978398 IFI44L IFIT4 MX1 0.978348 IFI44L OAS2 RIG1 0.978343 CIG5IFIT1 XIAP 0.978337 RIG1 OASL CHMP5 0.978325 IFI44L SAMD9L ZBP1 0.978297IFIT5 IFIT4 IFIT1 0.978296 OAS1 IRF7 TYKI 0.97822 IFIT5 OASL SAMD9L0.978202 IRF7 TYKI SP110 0.978191 SAMD9L MX1 RIGE 0.978177 IFIT5 OASLTYKI 0.978163 PARP9 SAMD9L XIAP 0.978139 G1P2 IFI44 OAS3 0.978119 OAS1HERC5 XIAP 0.97802 IFIT4 OAS2 SAMD9L 0.978019 IFI44L IRF7 HERC5 0.978014RIG1 OASL SAMD9L 0.97801 G1P2 MX1 ZBP1 0.977958 IFI44L OAS2 PARP90.977945 OAS3 SAMD9L TYKI 0.977935 PARP9 IFIT1 XIAP 0.977901 G1P2 OAS1OASL 0.977848 IFIT4 OAS2 OAS1 0.977813 IFI44 OAS3 SAMD9L 0.977801 IFI44TYKI RIGE 0.97779 IFIT5 SAMD9L ZBP1 0.977734 OAS2 EPSTI1 TYKI 0.977724PARP9 SAMD9L IFIT1 0.977718 RIG1 SAMD9L XIAP 0.977704 OAS3 TYKI IFIT10.977699 IFIT5 RIG1 OASL 0.977613 TYKI SP110 XIAP 0.977603 PARP9 TYKIIFIT1 0.977602 G1P2 OAS1 SAMD9L 0.977585 PARP9 TYKI XIAP 0.977542 OASLIFI44 TYKI 0.977504 IFIT5 IRF7 HERC5 0.977473 IRF7 IFI44 SP110 0.977459IFIT5 EPSTI1 TYKI 0.977454 IRF7 CIG5 IFIT1 0.977446 OAS2 OAS1 HERC50.977433 CIG5 TYKI CHMP5 0.977361 IFIT5 IFIT4 HERC5 0.977353 IFIT4EPSTI1 MX1 0.977281 IFI44L RIG1 SP110 0.977267 IFIT5 OASL PARP9 0.977265IFIT4 EPSTI1 IFIT1 0.977256 RIG1 IFIT1 MX1 0.977255 IFI44L IFIT4 HERC50.977207 IFIT4 G1P2 CIG5 0.977176 CIG5 IFI44 TYKI 0.9771 OAS1 TYKI ZBP10.977098 OAS2 G1P2 IFI44 0.977092 OASL SAMD9L CHMP5 0.977068 IFIT4 IFI44SP110 0.977067 G1P2 PARP9 SAMD9L 0.977067 IFIT4 CHMP5 ZBP1 0.977042 CIG5HERC5 CHMP5 0.976966 IFIT4 G1P2 OASL 0.976916 OAS2 G1P2 MX1 0.976841G1P2 IRF7 CIG5 0.97684 IFIT4 OAS1 PARP9 0.976808 OAS1 SAMD9L ZBP10.976794 IFIT4 OAS3 SAMD9L 0.976791 IFI44L IFIT1 XIAP 0.97677 IFI44LIRF7 IFIT1 0.976769 IFIT4 IFIT1 ZBP1 0.976725 G1P2 IFI44 SP110 0.976722OAS2 OAS1 TYKI 0.976711 IFIT5 OAS2 RIGE 0.976711 EPSTI1 G1P2 PARP90.97671 IFIT5 TYKI SP110 0.976687 G1P2 OAS3 SAMD9L 0.976675 RIG1 IFI44RIGE 0.976614 IFIT4 EPSTI1 IFI44 0.976597 RIG1 OAS3 CHMP5 0.976452EPSTI1 OAS1 SAMD9L 0.976439 RIG1 G1P2 CIG5 0.976418 CIG5 CHMP5 MX10.976409 OAS1 IRF7 SAMD9L 0.976378 OAS3 HERC5 IFIT1 0.976367 OAS2 IRF7SAMD9L 0.976358 IFIT5 IFIT4 G1P2 0.976294 EPSTI1 OAS1 IRF7 0.976291IFI44 HERC5 SP110 0.976272 IFI44 OAS3 RIGE 0.976262 IFIT4 G1P2 SP1100.976253 EPSTI1 G1P2 IFI44 0.976186 OASL IFIT1 XIAP 0.976181 IRF7 PARP9SAMD9L 0.976177 IRF7 HERC5 ZBP1 0.976154 OAS3 CHMP5 RIGE 0.976111 OASLTYKI XIAP 0.976092 IFI44L OAS2 SAMD9L 0.976088 IFI44L OAS1 OASL 0.976054IFIT1 MX1 SP110 0.976025 IFI44L HERC5 XIAP 0.975972 IFIT5 G1P2 XIAP0.975971 IFIT5 OAS2 SAMD9L 0.975959 IFIT5 HERC5 XIAP 0.975949 OASL IFI44SAMD9L 0.975842 IFIT5 EPSTI1 PARP9 0.975824 EPSTI1 IFI44 HERC5 0.975738SAMD9L TYKI RIGE 0.975714 IFI44 OAS3 TYKI 0.975702 IFIT5 TYKI RIGE0.97567 RIG1 CIG5 IFIT1 0.975658 HERC5 PARP9 SAMD9L 0.975637 G1P2 OAS3CHMP5 0.975579 OAS1 HERC5 TYKI 0.975575 IFIT5 OASL OAS3 0.975559 IFI44LIFIT4 IFIT1 0.975549 SAMD9L XIAP ZBP1 0.975489 EPSTI1 OASL TYKI 0.975407IFI44L EPSTI1 PARP9 0.975398 OASL IRF7 IFIT1 0.975396 RIG1 OAS1 CIG50.975346 RIG1 OASL IFIT1 0.975344 IFIT4 OAS1 OASL 0.975331 OAS3 HERC5TYKI 0.975303 OAS1 IFI44 RIGE 0.975295 OAS2 IFIT1 MX1 0.97529 IFIT1 MX1ZBP1 0.975252 CIG5 MX1 XIAP 0.975204 OAS1 CIG5 PARP9 0.97518 IFIT5 PARP9ZBP1 0.975163 IFI44L OAS1 ZBP1 0.97516 IFI44L EPSTI1 RIG1 0.975122 IFIT4OASL MX1 0.975118 OASL IRF7 TYKI 0.975116 OAS2 RIG1 TYKI 0.97509 OAS2CHMP5 XIAP 0.975079 OASL SAMD9L XIAP 0.975079 HERC5 PARP9 IFIT1 0.975059RIG1 G1P2 OAS1 0.975034 RIG1 OASL IFI44 0.974999 IFI44 OAS3 PARP90.974929 IFIT4 IFI44 XIAP 0.974925 IRF7 IFIT1 ZBP1 0.974912 PARP9 SAMD9LMX1 0.97489 OAS1 IFIT1 RIGE 0.974859 EPSTI1 SAMD9L ZBP1 0.974825 HERC5PARP9 XIAP 0.974823 EPSTI1 TYKI SP110 0.974822 IFIT4 CIG5 IFIT1 0.974778G1P2 OAS1 TYKI 0.974713 IFI44 IFIT1 SP110 0.974708 HERC5 PARP9 TYKI0.9747 EPSTI1 G1P2 ZBP1 0.974674 IFI44L OAS2 OAS1 0.974667 IFI44 TYKIZBP1 0.974642 EPSTI1 CHMP5 XIAP 0.974537 IFIT4 SAMD9L SP110 0.974501TYKI CHMP5 ZBP1 0.974475 EPSTI1 G1P2 CIG5 0.974468 OAS1 IFI44 OAS30.974458 EPSTI1 IFI44 IFIT1 0.974387 OAS1 OAS3 MX1 0.974382 OAS2 TYKIXIAP 0.974363 OAS1 OASL HERC5 0.974357 IFIT5 G1P2 IRF7 0.974308 OAS1OASL CHMP5 0.974297 TYKI IFIT1 RIGE 0.974282 OAS1 PARP9 MX1 0.974256OAS2 IFI44 TYKI 0.974177 OAS1 CIG5 IFI44 0.974175 RIG1 IFI44 OAS30.974125 IFI44L IFIT4 TYKI 0.974105 OAS1 CIG5 CHMP5 0.974105 OAS2 PARP9SAMD9L 0.974104 IRF7 CIG5 MX1 0.974084 CHMP5 SP110 XIAP 0.974042 EPSTI1CHMP5 SP110 0.973988 OAS1 TYKI XIAP 0.973951 HERC5 CHMP5 ZBP1 0.973937CIG5 TYKI ZBP1 0.973936 IFI44L SAMD9L SP110 0.973933 IFIT4 HERC5 PARP90.973933 IFIT5 OAS1 CIG5 0.97391 G1P2 PARP9 XIAP 0.973887 OAS1 CIG5 XIAP0.973886 CHMP5 MX1 ZBP1 0.973864 TYKI CHMP5 SP110 0.973768 EPSTI1 PARP9IFIT1 0.97373 IRF7 CHMP5 SP110 0.973693 CIG5 IFI44 PARP9 0.973655 G1P2PARP9 IFIT1 0.973599 EPSTI1 CIG5 SAMD9L 0.973586 G1P2 IRF7 ZBP1 0.97357EPSTI1 IRF7 CHMP5 0.973555 OASL IFI44 PARP9 0.973554 OAS2 TYKI CHMP50.973542 RIG1 G1P2 TYKI 0.973532 IRF7 IFI44 XIAP 0.973462 IFIT5 RIG1RIGE 0.973451 IFIT5 IFIT4 TYKI 0.973442 G1P2 HERC5 PARP9 0.97344 OAS2CHMP5 MX1 0.973422 PARP9 SAMD9L TYKI 0.973386 IFI44 MX1 XIAP 0.973355RIG1 SAMD9L TYKI 0.973328 CIG5 CHMP5 IFIT1 0.973246 CIG5 HERC5 PARP90.973244 IFI44L IFIT4 G1P2 0.973197 OASL IRF7 HERC5 0.973112 IFIT4 CIG5CHMP5 0.973104 OAS2 OAS1 SAMD9L 0.973103 G1P2 CIG5 CHMP5 0.973073 RIG1G1P2 SP110 0.973048 IFIT4 CIG5 MX1 0.973006 IFI44L EPSTI1 OAS1 0.973006IFIT4 OAS3 TYKI 0.973003 G1P2 XIAP ZBP1 0.97295 OASL PARP9 SAMD9L0.972938 EPSTI1 HERC5 PARP9 0.972841 IFIT1 XIAP ZBP1 0.972814 IFIT4PARP9 IFIT1 0.972796 CHMP5 MX1 SP110 0.972719 PARP9 TYKI MX1 0.972707IFIT4 MX1 ZBP1 0.972638 IFI44L EPSTI1 SAMD9L 0.972539 IFIT5 IFIT1 MX10.972533 IFI44L G1P2 XIAP 0.972515 EPSTI1 IFI44 TYKI 0.972495 IFIT4 OAS2HERC5 0.97249 IFIT4 RIG1 XIAP 0.97246 IFIT5 HERC5 MX1 0.972458 OAS1 TYKISP110 0.972445 EPSTI1 OAS1 CIG5 0.972368 CIG5 PARP9 IFIT1 0.972329 IFIT4OAS2 G1P2 0.972297 IFIT4 IRF7 IFI44 0.972137 HERC5 IFIT1 RIGE 0.97204IFI44L PARP9 RIGE 0.971994 RIG1 CIG5 MX1 0.971955 CIG5 IFI44 SAMD9L0.971908 CHMP5 IFIT1 ZBP1 0.971907 CIG5 SAMD9L ZBP1 0.971889 G1P2 OAS1PARP9 0.971807 IRF7 PARP9 IFIT1 0.97179 OAS3 TYKI MX1 0.971782 OAS2HERC5 CHMP5 0.97176 IRF7 HERC5 PARP9 0.971671 IFIT4 G1P2 PARP9 0.971625EPSTI1 TYKI CHMP5 0.971602 IRF7 IFI44 MX1 0.971595 OAS1 OASL SAMD9L0.971575 IFIT4 OAS2 CHMP5 0.971528 IFI44L G1P2 IRF7 0.971506 OAS1 HERC5SP110 0.971466 RIG1 OASL TYKI 0.971392 IRF7 PARP9 TYKI 0.971348 IFIT4OAS1 OAS3 0.971335 G1P2 CHMP5 ZBP1 0.971335 IFIT4 HERC5 SP110 0.971301IFI44 TYKI SP110 0.971298 OAS2 IRF7 HERC5 0.97127 IFIT4 OAS2 IFIT10.971233 IFI44L PARP9 SP110 0.971191 IFIT5 OAS1 OAS3 0.971185 OAS2 IRF7IFIT1 0.971184 OAS2 IFI44 PARP9 0.971174 IFI44L PARP9 ZBP1 0.971145 G1P2CHMP5 SP110 0.971088 OAS1 HERC5 SAMD9L 0.971083 G1P2 CIG5 PARP9 0.971042IFIT5 PARP9 XIAP 0.971027 EPSTI1 CHMP5 MX1 0.970954 G1P2 SP110 XIAP0.970897 OASL HERC5 XIAP 0.970881 RIG1 IFIT1 ZBP1 0.97081 G1P2 OASL XIAP0.970803 OAS2 PARP9 TYKI 0.970766 IFI44L IFIT4 OAS1 0.970742 IFIT5 G1P2MX1 0.970738 EPSTI1 CIG5 HERC5 0.970734 EPSTI1 OAS1 PARP9 0.970723 HERC5TYKI RIGE 0.970716 OAS1 OAS3 HERC5 0.970715 G1P2 IFIT1 RIGE 0.970712IFIT4 IRF7 XIAP 0.970712 HERC5 CHMP5 SP110 0.970697 IFI44L OAS3 RIGE0.970693 RIG1 CIG5 IFI44 0.970657 EPSTI1 OASL SAMD9L 0.970657 RIG1 G1P2ZBP1 0.970629 RIG1 HERC5 ZBP1 0.970593 IFI44 SAMD9L ZBP1 0.970587 OAS1IRF7 XIAP 0.970567 IFIT4 IFI44 MX1 0.970564 OAS1 OASL TYKI 0.970536 OAS1OASL IFI44 0.970435 OAS1 OAS3 SAMD9L 0.970395 OAS1 IRF7 ZBP1 0.970393IFI44L TYKI XIAP 0.970382 HERC5 XIAP ZBP1 0.970322 OAS2 CHMP5 IFIT10.970286 EPSTI1 OAS1 XIAP 0.970174 IFI44L IRF7 TYKI 0.970096 IFI44LHERC5 MX1 0.970092 PARP9 MX1 XIAP 0.970089 IFIT5 EPSTI1 RIG1 0.970015IFIT5 IFIT4 PARP9 0.97001 G1P2 OAS3 IFIT1 0.96993 OAS3 HERC5 MX10.969845 OASL MX1 XIAP 0.969812 OAS1 IFI44 ZBP1 0.969803 G1P2 HERC5 RIGE0.969762 IFIT5 PARP9 SP110 0.969753 G1P2 OAS3 HERC5 0.969712 OAS1 MX1RIGE 0.969615 HERC5 PARP9 MX1 0.969607 IFI44 IFIT1 XIAP 0.969589 RIG1OASL HERC5 0.969589 CIG5 TYKI SP110 0.969581 G1P2 IRF7 SP110 0.969568IFIT5 IFI44L RIGE 0.969542 IFI44 HERC5 XIAP 0.96949 RIG1 IFI44 ZBP10.969468 IFIT5 HERC5 IFIT1 0.969441 IRF7 IFI44 HERC5 0.96943 RIG1 OAS1HERC5 0.969339 IFIT5 TYKI XIAP 0.969273 EPSTI1 G1P2 OASL 0.969257 IFIT5G1P2 IFIT1 0.969226 TYKI MX1 RIGE 0.969116 OAS3 PARP9 CHMP5 0.969112EPSTI1 G1P2 CHMP5 0.96899 IFIT4 SAMD9L RIGE 0.968926 IFIT4 OAS1 SP1100.968908 OAS2 CIG5 TYKI 0.968886 EPSTI1 CIG5 IFIT1 0.968832 IFIT4 RIG1IRF7 0.968749 OASL IRF7 MX1 0.968693 IFIT4 IFIT1 SP110 0.968688 OAS2OAS1 IFI44 0.968687 OAS2 RIG1 SAMD9L 0.968678 IFIT5 EPSTI1 SAMD9L0.968673 OAS1 CHMP5 ZBP1 0.968667 IFI44L OAS1 SP110 0.968637 EPSTI1 RIG1OAS1 0.968633 G1P2 OAS1 OAS3 0.968589 IFIT4 IFI44 HERC5 0.968562 IFI44PARP9 RIGE 0.96854 IRF7 SAMD9L SP110 0.96853 OASL CIG5 TYKI 0.968523EPSTI1 HERC5 CHMP5 0.96846 OAS2 G1P2 CHMP5 0.968446 IRF7 OAS3 SAMD9L0.968439 G1P2 OASL IRF7 0.968413 EPSTI1 OASL IFIT1 0.968391 IFIT4 OAS3HERC5 0.968353 IFIT5 IRF7 TYKI 0.968333 RIG1 OAS1 IRF7 0.968329 EPSTI1IFIT1 ZBP1 0.968297 OASL CIG5 SAMD9L 0.968278 IRF7 MX1 ZBP1 0.968177OAS1 HERC5 PARP9 0.968172 G1P2 PARP9 TYKI 0.968154 CHMP5 IFIT1 SP1100.968058 IFIT4 CHMP5 SP110 0.968014 IFI44L IFIT1 MX1 0.967969 IFIT4 OAS2MX1 0.967961 IRF7 CHMP5 XIAP 0.967909 IFIT5 OAS1 ZBP1 0.967889 IRF7IFI44 IFIT1 0.967883 IFI44L HERC5 IFIT1 0.967852 OAS2 IFI44 SAMD9L0.967841 OAS2 G1P2 IRF7 0.967815 EPSTI1 PARP9 MX1 0.967795 EPSTI1 HERC5ZBP1 0.967772 OASL PARP9 CHMP5 0.967676 G1P2 IFI44 XIAP 0.967671 PARP9SAMD9L ZBP1 0.967633 IFIT5 TYKI MX1 0.967584 OAS2 EPSTI1 G1P2 0.967581IFIT4 OAS3 IFIT1 0.967551 IFIT5 OAS2 OAS1 0.967489 IFIT5 IFI44L OAS30.967466 OAS3 IFIT1 MX1 0.967409 IFIT5 SAMD9L SP110 0.967392 IFIT4 PARP9MX1 0.967359 EPSTI1 OAS1 ZBP1 0.967286 IFIT5 PARP9 RIGE 0.967265 OAS1SAMD9L XIAP 0.967252 PARP9 IFIT1 MX1 0.967202 OASL PARP9 IFIT1 0.967188IFIT4 PARP9 XIAP 0.967184 G1P2 OAS1 RIGE 0.967087 IFI44L PARP9 XIAP0.967006 IRF7 HERC5 SP110 0.966994 IFIT5 G1P2 HERC5 0.96692 IFI44L IFIT4SAMD9L 0.966918 EPSTI1 G1P2 SP110 0.966913 IFIT4 EPSTI1 CHMP5 0.966844OAS2 OAS1 CHMP5 0.966812 EPSTI1 IFI44 PARP9 0.966774 IFIT4 IFI44 IFIT10.966763 CIG5 SAMD9L CHMP5 0.966661 IFI44L IFIT4 PARP9 0.966617 IFIT5RIG1 SP110 0.966575 EPSTI1 CIG5 MX1 0.966555 EPSTI1 CHMP5 IFIT1 0.966528OAS2 IFIT1 XIAP 0.966404 MX1 XIAP ZBP1 0.966334 HERC5 MX1 RIGE 0.966315IFIT5 OAS1 RIGE 0.966293 G1P2 PARP9 MX1 0.966277 IFI44L TYKI MX1 0.96627IFI44 PARP9 ZBP1 0.966234 OAS1 CIG5 ZBP1 0.966217 IFIT4 G1P2 IFI440.966203 IFIT4 MX1 SP110 0.966196 OAS2 OAS1 IRF7 0.966139 IFIT4 CHMP5XIAP 0.966104 IFIT5 IFIT4 SAMD9L 0.966044 RIG1 OASL MX1 0.966034 IFIT5IRF7 PARP9 0.96594 G1P2 IRF7 PARP9 0.965876 OAS2 RIG1 IFI44 0.965818IFI44L G1P2 MX1 0.96579 IRF7 IFIT1 SP110 0.965745 OAS2 EPSTI1 SAMD9L0.965666 CHMP5 MX1 XIAP 0.965604 OAS2 PARP9 IFIT1 0.965491 EPSTI1 OAS1IFI44 0.96548 OAS2 IRF7 MX1 0.965404 OAS1 SAMD9L RIGE 0.965336 IFIT1SP110 XIAP 0.965321 RIG1 G1P2 OASL 0.965315 IFI44L OAS1 MX1 0.965307G1P2 IRF7 IFI44 0.965102 IFIT5 TYKI IFIT1 0.965094 IFI44L G1P2 HERC50.965057 IFI44L G1P2 IFIT1 0.965022 IFIT5 SP110 RIGE 0.965009 EPSTI1OASL HERC5 0.964998 OAS2 RIG1 IFIT1 0.964968 IFI44L IRF7 SAMD9L 0.964937OAS3 PARP9 SAMD9L 0.964908 IFIT4 IFI44 TYKI 0.964883 PARP9 TYKI SP1100.964876 IFIT5 IFIT4 RIG1 0.964868 EPSTI1 OAS3 TYKI 0.964834 IFI44LIFIT4 RIG1 0.964794 IFIT1 MX1 RIGE 0.96478 OAS2 SAMD9L XIAP 0.964778IFIT5 IFIT4 OAS1 0.964745 OASL PARP9 TYKI 0.96474 OAS1 SAMD9L TYKI0.964718 EPSTI1 OAS3 SAMD9L 0.964666 CIG5 PARP9 MX1 0.96462 OAS2 G1P2XIAP 0.964584 G1P2 TYKI RIGE 0.964575 OAS1 OAS3 TYKI 0.964457 SAMD9LCHMP5 ZBP1 0.964434 IFI44L TYKI IFIT1 0.964427 G1P2 OAS3 TYKI 0.964415IFIT4 TYKI RIGE 0.964415 IFIT5 PARP9 IFIT1 0.964404 IFI44 HERC5 MX10.964284 IFI44L OAS1 IRF7 0.964253 OAS1 IRF7 PARP9 0.964194 IFIT5 OASLRIGE 0.964094 IFIT5 PARP9 MX1 0.963954 G1P2 CIG5 ZBP1 0.963938 IFIT5OAS1 OASL 0.963852 IRF7 CHMP5 MX1 0.963787 IFIT5 EPSTI1 OAS1 0.963774OAS1 PARP9 XIAP 0.963475 OAS1 HERC5 RIGE 0.963465 EPSTI1 MX1 ZBP10.963452 EPSTI1 OASL MX1 0.963447 IRF7 PARP9 MX1 0.963413 IFI44 TYKIXIAP 0.963301 G1P2 MX1 RIGE 0.96322 EPSTI1 IFI44 SAMD9L 0.963203 OAS1PARP9 SAMD9L 0.963196 IFI44L OAS1 IFIT1 0.963135 IFI44L IRF7 PARP90.963058 OAS1 SAMD9L SP110 0.963012 IFIT5 IRF7 SAMD9L 0.963 EPSTI1 OAS1CHMP5 0.962935 IFIT4 IRF7 CHMP5 0.962925 IFIT4 EPSTI1 XIAP 0.96284 CIG5HERC5 ZBP1 0.962817 PARP9 TYKI ZBP1 0.96278 OASL CIG5 IFIT1 0.962747OAS1 PARP9 TYKI 0.962615 IFI44L HERC5 TYKI 0.962603 OAS2 EPSTI1 IFIT10.962552 CIG5 PARP9 CHMP5 0.962508 IFI44L RIG1 IRF7 0.962495 IFI44LSAMD9L XIAP 0.962462 IFI44L IFI44 RIGE 0.9624 IRF7 HERC5 CHMP5 0.962383OASL SAMD9L ZBP1 0.962363 OAS2 CIG5 SAMD9L 0.962348 OAS2 RIG1 HERC50.962318 OAS2 HERC5 XIAP 0.962291 IFIT5 SAMD9L MX1 0.962201 CIG5 IFIT1ZBP1 0.962115 HERC5 SP110 XIAP 0.962086 RIG1 IFIT1 SP110 0.962019 OAS2OAS1 PARP9 0.962018 RIG1 CIG5 CHMP5 0.961991 IFI44 IFIT1 MX1 0.961953IFIT5 OAS1 MX1 0.961952 HERC5 CHMP5 XIAP 0.961934 RIG1 HERC5 SP1100.961903 OAS3 SAMD9L XIAP 0.961841 RIG1 SAMD9L SP110 0.961804 CHMP5IFIT1 XIAP 0.961773 G1P2 OAS3 MX1 0.961665 TYKI CHMP5 XIAP 0.961658 TYKISP110 ZBP1 0.961568 OAS2 HERC5 PARP9 0.961517 G1P2 IFI44 MX1 0.961483IFIT4 OAS1 IFI44 0.961474 IRF7 IFI44 TYKI 0.961401 IFI44L RIG1 XIAP0.961392 SAMD9L SP110 XIAP 0.961343 PARP9 SAMD9L SP110 0.961334 IFIT5IFI44L OASL 0.961265 OAS2 G1P2 PARP9 0.961245 OASL HERC5 PARP9 0.961238RIG1 MX1 ZBP1 0.96122 OAS2 RIG1 G1P2 0.961201 IRF7 OAS3 IFIT1 0.961186OAS2 EPSTI1 OAS1 0.96115 IFI44 SAMD9L SP110 0.961138 OAS1 XIAP ZBP10.961114 IFIT4 G1P2 OAS3 0.961085 IFIT5 RIG1 XIAP 0.961054 IFIT5 SAMD9LXIAP 0.961053 IFI44 HERC5 IFIT1 0.960963 IFIT5 RIG1 IRF7 0.96093 IFI44LCHMP5 RIGE 0.960881 IFIT4 OAS3 MX1 0.960838 IFIT5 OAS3 RIGE 0.960806OAS2 EPSTI1 HERC5 0.960756 OAS2 MX1 XIAP 0.960748 IFIT4 TYKI CHMP50.960741 EPSTI1 RIG1 IFI44 0.960722 IFIT5 HERC5 TYKI 0.960702 OASL CIG5HERC5 0.960689 IFI44L SAMD9L MX1 0.960664 IFIT5 IFI44L CIG5 0.960571IFIT4 EPSTI1 IRF7 0.960461 IRF7 MX1 SP110 0.96046 IFI44L OAS1 XIAP0.960455 IFIT5 CHMP5 RIGE 0.960416 IFIT5 IFI44 RIGE 0.960385 IFIT5 RIG1MX1 0.960368 MX1 SP110 XIAP 0.960338 IRF7 OAS3 HERC5 0.960332 IRF7 OAS3TYKI 0.960205 IFI44 PARP9 SP110 0.960125 OASL TYKI ZBP1 0.960125 IRF7CHMP5 IFIT1 0.960021 OAS2 SAMD9L CHMP5 0.959993 G1P2 IFI44 HERC50.959978 IFIT4 CHMP5 MX1 0.959927 IFI44 TYKI MX1 0.959842 G1P2 OASL CIG50.959832 IFIT4 CIG5 XIAP 0.959816 IFIT4 OAS1 RIGE 0.959814 OAS2 TYKIZBP1 0.959811 IRF7 TYKI CHMP5 0.959787 OAS3 IFIT1 XIAP 0.959775 OAS2OAS1 CIG5 0.959672 G1P2 CHMP5 XIAP 0.959471 G1P2 IFI44 IFIT1 0.959467IFI44L PARP9 IFIT1 0.959464 G1P2 OASL PARP9 0.959415 IFIT5 HERC5 PARP90.959387 OAS1 OASL IRF7 0.959375 OAS1 IFI44 SP110 0.959304 IFI44 PARP9XIAP 0.959285 IFIT5 OAS1 IFIT1 0.959283 PARP9 CHMP5 RIGE 0.959251 OAS3TYKI XIAP 0.959059 IFIT5 IFI44 OAS3 0.959005 IFIT5 OAS3 CHMP5 0.959002RIG1 CHMP5 ZBP1 0.958994 IFIT4 IFIT1 RIGE 0.958926 EPSTI1 PARP9 XIAP0.958805 RIG1 OAS1 ZBP1 0.958689 OAS1 IFI44 MX1 0.958663 EPSTI1 OAS3IFIT1 0.958634 IFIT5 G1P2 PARP9 0.95861 OAS2 EPSTI1 MX1 0.958508 PARP9IFIT1 ZBP1 0.958503 IFIT4 HERC5 CHMP5 0.958451 G1P2 CIG5 SP110 0.958403IFI44L PARP9 MX1 0.958264 OAS1 CHMP5 SP110 0.95826 G1P2 PARP9 SP1100.958153 OAS1 TYKI RIGE 0.958151 IFIT4 HERC5 RIGE 0.958132 RIG1 OAS1TYKI 0.958104 IFIT4 IRF7 PARP9 0.958024 IFIT4 EPSTI1 PARP9 0.957986IFIT5 SAMD9L IFIT1 0.957766 RIG1 IRF7 XIAP 0.957764 CIG5 SAMD9L SP1100.957721 IFI44L IFI44 OAS3 0.957601 IFIT5 G1P2 TYKI 0.9576 IFI44L HERC5PARP9 0.957553 RIG1 OAS3 SAMD9L 0.957356 EPSTI1 OAS1 OASL 0.957294 IFIT4XIAP ZBP1 0.95721 IFI44L SAMD9L IFIT1 0.957107 IFI44L G1P2 TYKI 0.957049OAS2 RIG1 MX1 0.957032 IFI44 TYKI IFIT1 0.957022 CIG5 PARP9 XIAP0.957014 IFIT4 IRF7 ZBP1 0.956993 IFI44L G1P2 OAS1 0.956925 OAS1 OASLCIG5 0.956894 IFIT4 IFI44 PARP9 0.95679 EPSTI1 OAS3 HERC5 0.956754 IFIT4G1P2 RIGE 0.956716 IFIT4 IRF7 CIG5 0.956703 IFIT4 OAS1 CHMP5 0.956662IFI44L OAS1 HERC5 0.956626 G1P2 IRF7 CHMP5 0.956597 IFIT4 IFI44 SAMD9L0.956274 IFIT5 IFI44L ZBP1 0.956233 IFI44L RIG1 MX1 0.956172 IFIT4 CHMP5IFIT1 0.95615 IFIT5 OAS1 IRF7 0.956078 OASL CIG5 MX1 0.956076 OASL IFIT1ZBP1 0.956072 OAS2 G1P2 CIG5 0.956019 OAS2 PARP9 CHMP5 0.956009 G1P2PARP9 ZBP1 0.955951 OAS2 OASL TYKI 0.955901 OAS1 IRF7 IFI44 0.955882IFI44 HERC5 TYKI 0.955752 OAS3 HERC5 XIAP 0.955729 RIG1 PARP9 IFIT10.955722 OAS2 CIG5 IFIT1 0.955705 IFIT4 OASL XIAP 0.955698 IFIT4 CIG5PARP9 0.955687 OASL PARP9 MX1 0.955668 PARP9 IFIT1 SP110 0.955597 IFIT4EPSTI1 RIG1 0.95557 EPSTI1 OAS1 OAS3 0.955534 OAS2 TYKI SP110 0.955523IFIT4 G1P2 CHMP5 0.955509 OAS1 IFI44 IFIT1 0.955489 IFIT5 IFI44L OAS20.955474 RIG1 IFI44 SP110 0.955462 IFIT5 G1P2 SAMD9L 0.955415 RIG1 MX1SP110 0.955384 CIG5 MX1 ZBP1 0.955366 IFI44L HERC5 SAMD9L 0.955348EPSTI1 SAMD9L CHMP5 0.955332 RIG1 OAS1 XIAP 0.955331 EPSTI1 IRF7 XIAP0.95532 IFIT5 RIG1 IFIT1 0.955282 EPSTI1 SAMD9L SP110 0.955279 EPSTI1G1P2 OAS3 0.955231 OAS2 CIG5 HERC5 0.955226 TYKI CHMP5 MX1 0.955217IFI44L OAS3 CHMP5 0.955174 SAMD9L RIGE XIAP 0.955126 OAS3 PARP9 IFIT10.955055 RIG1 PARP9 SAMD9L 0.955049 HERC5 PARP9 ZBP1 0.954901 OAS2SAMD9L ZBP1 0.954865 EPSTI1 IFIT1 SP110 0.954814 IFIT5 OAS1 SP1100.954676 OAS1 PARP9 ZBP1 0.954667 SAMD9L CHMP5 SP110 0.954657 IFI44LG1P2 SAMD9L 0.954471 IRF7 PARP9 XIAP 0.954463 CIG5 OAS3 SAMD9L 0.95446OAS1 IRF7 OAS3 0.954415 HERC5 CHMP5 MX1 0.954364 OAS1 IFI44 XIAP0.954344 IRF7 IFI44 SAMD9L 0.954318 OAS1 OASL XIAP 0.954263 IFI44L OASLIFI44 0.954204 IFI44 SAMD9L XIAP 0.954127 OAS2 PARP9 MX1 0.9541 OAS1CHMP5 MX1 0.95402 OAS2 OASL SAMD9L 0.953851 IRF7 IFI44 PARP9 0.953769OAS2 OAS1 XIAP 0.953577 IFI44L G1P2 PARP9 0.953542 EPSTI1 HERC5 SP1100.953434 IRF7 SAMD9L RIGE 0.953308 EPSTI1 PARP9 CHMP5 0.953256 OAS1 IRF7CHMP5 0.953118 IFIT5 HERC5 SAMD9L 0.95311 IFIT5 G1P2 OAS1 0.953008 IFI44SAMD9L MX1 0.952969 IFIT5 OAS1 XIAP 0.952878 IFIT4 MX1 RIGE 0.952876IFI44L RIG1 IFIT1 0.952657 CIG5 HERC5 SP110 0.95255 IFIT4 OASL IRF70.952437 IFIT5 PARP9 TYKI 0.952387 OAS1 OASL PARP9 0.952351 IFIT5 OASLIFI44 0.952334 TYKI CHMP5 IFIT1 0.952291 EPSTI1 IRF7 PARP9 0.95219 IRF7CIG5 XIAP 0.952171 IFIT1 RIGE XIAP 0.952097 CIG5 IFIT1 SP110 0.952015G1P2 OASL ZBP1 0.951985 EPSTI1 RIG1 IRF7 0.951946 IFI44L PARP9 TYKI0.951921 IFI44 PARP9 MX1 0.951919 OAS3 PARP9 TYKI 0.951916 CIG5 OAS3TYKI 0.951891 G1P2 IFI44 TYKI 0.951838 OAS2 RIG1 CHMP5 0.951825 EPSTI1TYKI RIGE 0.951667 RIG1 PARP9 TYKI 0.951655 HERC5 PARP9 SP110 0.951639IFIT4 RIG1 ZBP1 0.951613 RIG1 HERC5 PARP9 0.951503 G1P2 OAS1 IFI440.951439 IRF7 OAS3 MX1 0.951423 IFI44 PARP9 IFIT1 0.95141 CHMP5 IFIT1MX1 0.951388 EPSTI1 MX1 SP110 0.951254 OAS2 RIG1 OAS1 0.951245 IFI44LRIG1 HERC5 0.951245 IFIT5 CIG5 IFI44 0.951244 TYKI RIGE XIAP 0.951171EPSTI1 SAMD9L RIGE 0.951147 HERC5 TYKI CHMP5 0.951145 EPSTI1 OAS3 MX10.951138 HERC5 CHMP5 IFIT1 0.951107 IFI44L CIG5 IFI44 0.951044 IFI44LOASL CHMP5 0.951043 G1P2 SP110 ZBP1 0.951027 SAMD9L SP110 ZBP1 0.95089G1P2 CHMP5 MX1 0.950868 OAS2 OASL IFIT1 0.950862 PARP9 CHMP5 ZBP10.950852 OAS3 HERC5 PARP9 0.95078 EPSTI1 RIG1 XIAP 0.950771 OASL TYKISP110 0.950742 IFIT4 RIG1 CIG5 0.950667 OAS1 IRF7 SP110 0.950651 OAS1CHMP5 IFIT1 0.950645 IFIT5 IFI44L EPSTI1 0.950585 IFIT5 OASL CHMP50.950564 OAS1 CHMP5 XIAP 0.950413 OAS3 MX1 XIAP 0.950368 OASL HERC5 ZBP10.950235 IFI44 HERC5 PARP9 0.950187 OAS1 IFI44 HERC5 0.95016 RIG1 OAS1SAMD9L 0.950071 G1P2 HERC5 CHMP5 0.949965 RIG1 OAS3 IFIT1 0.9499 IRF7CIG5 PARP9 0.949776 IFI44L SAMD9L TYKI 0.949773 IFI44 CHMP5 RIGE0.949687 G1P2 OAS3 XIAP 0.949642 OAS1 CIG5 SP110 0.949578 OAS2 CIG5 MX10.949555 IFIT5 OAS1 HERC5 0.949513 OAS1 OAS3 PARP9 0.94951 G1P2 IRF7OAS3 0.949402 G1P2 CHMP5 IFIT1 0.949251 IFIT5 RIG1 HERC5 0.948959 IFIT4RIG1 IFI44 0.948886 IFI44L OAS1 TYKI 0.948871 RIG1 IFI44 XIAP 0.94863IFIT5 PARP9 SAMD9L 0.948596 IFI44 SAMD9L IFIT1 0.948585 IFIT4 OASL PARP90.948562 IFIT4 EPSTI1 ZBP1 0.948539 IFIT5 RIG1 G1P2 0.948086 OAS1 CIG5OAS3 0.947983 G1P2 IFI44 PARP9 0.947968 IFIT5 IFI44L SP110 0.947938EPSTI1 CIG5 PARP9 0.947921 EPSTI1 RIG1 CHMP5 0.947831 IFIT5 IFI44 ZBP10.947787 IFI44L PARP9 SAMD9L 0.947734 G1P2 IFI44 SAMD9L 0.947721 IFI44LOAS1 PARP9 0.947446 IFI44 HERC5 SAMD9L 0.947347 OAS2 IFIT1 ZBP1 0.947303IFIT4 EPSTI1 CIG5 0.947143 RIG1 G1P2 PARP9 0.947042 IFIT4 RIG1 OASL0.946997 OAS2 G1P2 ZBP1 0.946916 CIG5 OAS3 IFIT1 0.946822 G1P2 RIGE XIAP0.946802 OAS1 OAS3 XIAP 0.946769 IFIT5 SAMD9L TYKI 0.946742 RIG1 CIG5XIAP 0.946738 CIG5 SAMD9L RIGE 0.946558 IRF7 IFIT1 RIGE 0.946462 IFI44LIFI44 ZBP1 0.946452 PARP9 MX1 ZBP1 0.946362 IFIT5 OAS2 IFI44 0.946333EPSTI1 G1P2 RIGE 0.946322 HERC5 RIGE XIAP 0.946188 CIG5 MX1 SP1100.946153 RIG1 SAMD9L RIGE 0.946083 RIG1 IRF7 IFI44 0.946068 IRF7 SAMD9LCHMP5 0.946026 G1P2 TYKI CHMP5 0.945962 RIG1 OAS3 HERC5 0.945918 RIG1IRF7 CIG5 0.945803 OASL MX1 ZBP1 0.945774 G1P2 OAS1 CHMP5 0.945734 IFIT4OAS2 IRF7 0.945691 CIG5 OAS3 HERC5 0.945585 IFIT4 SAMD9L CHMP5 0.945499IFIT5 CIG5 CHMP5 0.945489 EPSTI1 OAS1 SP110 0.945479 IRF7 TYKI RIGE0.945447 RIG1 IFI44 MX1 0.945413 EPSTI1 IFIT1 RIGE 0.945395 IFIT4 OAS2PARP9 0.945338 IFI44L RIG1 G1P2 0.945334 IFI44 OAS3 CHMP5 0.945317 OAS2OAS1 ZBP1 0.945291 RIG1 OAS3 TYKI 0.945221 SAMD9L CHMP5 XIAP 0.945205PARP9 SAMD9L RIGE 0.945185 OAS2 G1P2 OASL 0.944851 PARP9 CHMP5 XIAP0.944816 IFIT4 EPSTI1 OASL 0.944671 IFI44L OAS2 IFI44 0.944632 IFIT4PARP9 ZBP1 0.944622 EPSTI1 CIG5 XIAP 0.944456 RIG1 OAS1 OASL 0.944438OAS1 HERC5 CHMP5 0.94431 IFI44 PARP9 TYKI 0.944208 PARP9 CHMP5 SP1100.944124 IFIT1 SP110 ZBP1 0.944046 IFI44L CIG5 CHMP5 0.943778 IFIT5IFI44L IFIT4 0.943771 PARP9 MX1 SP110 0.943665 RIG1 CHMP5 SP110 0.943533OAS2 OASL HERC5 0.9435 OAS1 OASL ZBP1 0.9435 IFIT4 OAS2 XIAP 0.943449MX1 RIGE XIAP 0.943426 CIG5 TYKI RIGE 0.943328 EPSTI1 IRF7 CIG5 0.943287IRF7 HERC5 RIGE 0.943132 RIG1 PARP9 MX1 0.942814 OAS2 HERC5 ZBP10.942715 IFIT4 RIG1 PARP9 0.942684 SAMD9L CHMP5 MX1 0.942597 OASL SAMD9LSP110 0.942585 G1P2 OAS3 PARP9 0.942554 OAS1 IFI44 TYKI 0.942437 OASLIFIT1 SP110 0.942318 IFI44L EPSTI1 IFI44 0.942267 OAS3 SAMD9L ZBP10.942149 OAS1 PARP9 SP110 0.942068 OAS1 SP110 XIAP 0.942012 IFI44L RIG1TYKI 0.94201 IFIT5 OAS1 PARP9 0.94199 G1P2 OASL SP110 0.941717 IFI44SAMD9L TYKI 0.941631 IFIT4 CIG5 ZBP1 0.941466 EPSTI1 HERC5 RIGE 0.941431IFIT5 OAS1 TYKI 0.941419 IFIT5 EPSTI1 IFI44 0.941395 IFI44L OAS1 SAMD9L0.941117 OAS2 OASL MX1 0.941065 IFIT5 CHMP5 ZBP1 0.940941 OAS2 G1P2SP110 0.940753 OAS3 PARP9 MX1 0.940695 OASL IFI44 CHMP5 0.940462 RIG1IFI44 IFIT1 0.940444 IRF7 XIAP ZBP1 0.940387 IFIT4 OAS3 XIAP 0.940303OAS1 TYKI CHMP5 0.940259 HERC5 SP110 ZBP1 0.940142 G1P2 CIG5 OAS30.939919 OAS1 IFI44 PARP9 0.939836 IFIT4 PARP9 CHMP5 0.9396 RIG1 IFI44HERC5 0.939599 IFIT4 IRF7 OAS3 0.939488 G1P2 IRF7 RIGE 0.939474 IFIT5IFI44L XIAP 0.939166 EPSTI1 OAS1 RIGE 0.938921 RIG1 PARP9 XIAP 0.938797EPSTI1 IRF7 ZBP1 0.938775 IFIT5 OAS2 CHMP5 0.938637 IFIT4 OASL CIG50.938552 EPSTI1 MX1 RIGE 0.938432 IFIT5 IFI44L IRF7 0.938421 OASL PARP9XIAP 0.938359 IFIT5 IFI44L MX1 0.93825 CIG5 IFIT1 RIGE 0.938229 EPSTI1RIG1 PARP9 0.938162 IFIT5 RIG1 TYKI 0.938067 IFI44 PARP9 SAMD9L 0.937964IRF7 PARP9 CHMP5 0.937956 SAMD9L CHMP5 IFIT1 0.937945 IFI44L IFI44 SP1100.937911 OAS3 TYKI ZBP1 0.937748 IFIT4 OAS3 PARP9 0.937712 CIG5 OAS3 MX10.937685 IFI44L CHMP5 ZBP1 0.937606 RIG1 OAS1 PARP9 0.937438 OAS2 SAMD9LSP110 0.937426 IRF7 MX1 RIGE 0.937279 OAS2 OAS1 OASL 0.937248 RIG1 IFIT1RIGE 0.93718 OAS2 MX1 ZBP1 0.937132 G1P2 SAMD9L CHMP5 0.936982 EPSTI1XIAP ZBP1 0.936697 RIG1 G1P2 IFI44 0.936637 OAS1 CIG5 RIGE 0.936614 OASLIRF7 XIAP 0.936603 PARP9 IFIT1 RIGE 0.936593 HERC5 SAMD9L CHMP5 0.93654IFIT4 SP110 XIAP 0.936501 IFIT4 OAS2 EPSTI1 0.936231 RIG1 CIG5 PARP90.936225 IFIT4 EPSTI1 OAS3 0.936192 IFIT5 IFI44 SP110 0.936081 PARP9CHMP5 IFIT1 0.935858 SAMD9L TYKI CHMP5 0.935842 OAS2 IFIT1 SP1100.935741 OAS1 IRF7 RIGE 0.935686 OASL OAS3 SAMD9L 0.935639 CIG5 HERC5RIGE 0.935444 OAS1 RIGE XIAP 0.935361 G1P2 CIG5 RIGE 0.935304 IFIT5IFI44L IFIT1 0.935275 PARP9 CHMP5 MX1 0.935232 RIG1 OAS3 MX1 0.935175IFI44L OAS2 CHMP5 0.934781 RIG1 OAS1 OAS3 0.934681 OASL HERC5 SP1100.934566 PARP9 TYKI CHMP5 0.934504 OAS3 IFIT1 ZBP1 0.934375 SAMD9L RIGEZBP1 0.934283 HERC5 PARP9 CHMP5 0.93411 IFIT5 IFIT4 IFI44 0.934012EPSTI1 OASL PARP9 0.933922 OAS3 TYKI SP110 0.933864 CIG5 IFI44 CHMP50.933838 MX1 SP110 ZBP1 0.933692 RIG1 CHMP5 XIAP 0.933629 OAS1 IFI44SAMD9L 0.933607 IFI44L IFIT4 IFI44 0.933553 PARP9 TYKI RIGE 0.933515IFIT4 IRF7 SP110 0.933498 OAS2 EPSTI1 PARP9 0.933446 OAS1 SP110 ZBP10.933405 OAS2 PARP9 XIAP 0.933338 IFIT5 EPSTI1 CHMP5 0.933165 EPSTI1OASL XIAP 0.933115 IFIT4 OASL ZBP1 0.933099 EPSTI1 PARP9 ZBP1 0.932945IFI44L EPSTI1 CHMP5 0.932873 OASL OAS3 IFIT1 0.932774 PARP9 XIAP ZBP10.932749 EPSTI1 RIG1 CIG5 0.93261 IFIT5 OAS1 SAMD9L 0.932602 OASL MX1SP110 0.932194 IFIT4 OAS2 RIG1 0.932084 RIG1 TYKI RIGE 0.932067 RIG1IRF7 ZBP1 0.931911 EPSTI1 OASL IRF7 0.931811 RIG1 G1P2 OAS3 0.931711OAS2 IRF7 PARP9 0.931653 IFI44L RIG1 OAS1 0.931497 G1P2 PARP9 CHMP50.931468 IFIT5 RIG1 PARP9 0.931134 IFIT5 IFI44L HERC5 0.931073 RIG1 IRF7CHMP5 0.930931 IFIT5 IFI44 XIAP 0.930929 OAS3 SAMD9L SP110 0.930851 OASLOAS3 TYKI 0.930816 IFIT5 IFI44 MX1 0.930811 IRF7 CIG5 ZBP1 0.930782 RIG1IFI44 TYKI 0.930705 IFI44L IFI44 XIAP 0.930504 OASL IRF7 PARP9 0.930323CIG5 XIAP ZBP1 0.930024 IFIT5 IFI44L G1P2 0.929939 OAS1 OAS3 ZBP10.92992 IFIT4 RIG1 CHMP5 0.929849 OAS2 HERC5 SP110 0.929752 CIG5 MX1RIGE 0.929631 RIG1 HERC5 RIGE 0.929627 HERC5 PARP9 RIGE 0.929502 IFI44LRIG1 SAMD9L 0.929277 OAS3 HERC5 ZBP1 0.929262 IFIT4 PARP9 SP110 0.929202IFI44L IFI44 MX1 0.929036 OAS1 PARP9 CHMP5 0.928969 IFI44L IRF7 IFI440.928905 TYKI RIGE ZBP1 0.928873 IFIT5 IRF7 IFI44 0.928864 IFIT4 OAS2CIG5 0.928862 G1P2 PARP9 RIGE 0.928789 IFI44L RIG1 PARP9 0.928757 IFI44CHMP5 ZBP1 0.928586 OAS2 OAS3 TYKI 0.928574 OASL CIG5 PARP9 0.928457IFI44L CHMP5 SP110 0.928425 IFIT5 CHMP5 SP110 0.92804 OAS2 OAS3 SAMD9L0.928004 RIG1 OAS1 SP110 0.927916 IRF7 PARP9 ZBP1 0.927757 RIG1 CHMP5MX1 0.927685 OASL CIG5 XIAP 0.927452 IFIT5 IFI44 IFIT1 0.927301 RIG1G1P2 RIGE 0.927147 OAS1 PARP9 RIGE 0.926871 CIG5 PARP9 ZBP1 0.926818OAS2 EPSTI1 IRF7 0.926537 OAS3 IFIT1 SP110 0.926516 OAS2 IRF7 XIAP0.926247 OAS2 MX1 SP110 0.926135 IFI44L IFI44 IFIT1 0.926123 OAS1 SAMD9LCHMP5 0.925906 OAS2 CIG5 PARP9 0.925828 EPSTI1 OAS3 PARP9 0.925671 G1P2OAS3 ZBP1 0.925573 IFIT1 RIGE ZBP1 0.925539 IFIT4 RIGE XIAP 0.925317OAS2 IFI44 CHMP5 0.925256 RIG1 XIAP ZBP1 0.925255 OASL IRF7 CIG50.925231 OASL OAS3 HERC5 0.92508 IFIT5 IFI44L TYKI 0.924932 EPSTI1 RIG1ZBP1 0.924695 IFIT5 RIG1 SAMD9L 0.924337 OAS2 OAS3 IFIT1 0.924255 IFI44LIFI44 HERC5 0.924174 RIG1 IRF7 PARP9 0.923945 EPSTI1 CIG5 ZBP1 0.923914OAS2 OAS1 SP110 0.923858 IFIT5 IFI44 HERC5 0.923703 IFIT5 G1P2 IFI440.923603 RIG1 MX1 RIGE 0.923568 IFIT4 CIG5 OAS3 0.92356 IFIT5 IFIT4CHMP5 0.923303 EPSTI1 IFI44 CHMP5 0.923176 IFIT4 RIG1 OAS3 0.923081 RIG1OASL XIAP 0.922837 RIG1 CHMP5 IFIT1 0.922695 PARP9 MX1 RIGE 0.922687OAS2 SAMD9L RIGE 0.922634 IFIT5 IFI44L PARP9 0.92262 IFIT4 EPSTI1 SP1100.922466 IFI44L G1P2 IFI44 0.922343 OAS3 PARP9 XIAP 0.921953 OAS2 EPSTI1XIAP 0.921908 OAS2 TYKI RIGE 0.921747 IFIT4 OAS2 ZBP1 0.921651 RIG1HERC5 CHMP5 0.92161 IFI44L IFIT4 CHMP5 0.921594 EPSTI1 IRF7 OAS30.921499 RIG1 OASL IRF7 0.921365 G1P2 RIGE ZBP1 0.921333 PARP9 SAMD9LCHMP5 0.92129 IFIT5 CHMP5 XIAP 0.921284 OAS3 MX1 ZBP1 0.921266 RIG1 TYKICHMP5 0.92113 IFIT4 OAS2 OASL 0.921102 RIG1 OAS1 IFI44 0.921011 OASLSAMD9L RIGE 0.92072 OAS3 HERC5 SP110 0.920417 EPSTI1 OAS3 XIAP 0.920342IFIT5 CHMP5 MX1 0.920248 OASL OAS3 MX1 0.920206 G1P2 OAS3 SP110 0.920122G1P2 OASL OAS3 0.920062 IFIT4 CIG5 SP110 0.919544 IFI44L CHMP5 XIAP0.919301 EPSTI1 OASL CIG5 0.91928 OAS1 OASL SP110 0.919179 IFIT5 IRF7CHMP5 0.919067 OAS2 OAS1 OAS3 0.918994 IFI44L IFI44 TYKI 0.918961 OAS1OASL OAS3 0.918852 HERC5 RIGE ZBP1 0.918551 OASL IFIT1 RIGE 0.91841IFIT5 RIG1 OAS1 0.91814 OAS2 IRF7 CIG5 0.918041 IRF7 OAS3 XIAP 0.918037IFIT5 IFI44 TYKI 0.917786 OAS1 RIGE ZBP1 0.917732 RIG1 G1P2 CHMP50.917667 IFI44L IRF7 CHMP5 0.917628 OAS2 IFIT1 RIGE 0.917465 OAS2 OAS3HERC5 0.91737 IRF7 OAS3 PARP9 0.917026 IFI44L CHMP5 MX1 0.916997 IFIT4IRF7 RIGE 0.916887 IFIT4 RIG1 SP110 0.916864 IFIT5 CHMP5 IFIT1 0.916571OASL TYKI RIGE 0.916429 IFIT4 EPSTI1 RIGE 0.916258 EPSTI1 RIG1 OASL0.916184 RIG1 IFI44 PARP9 0.916107 IFIT5 IFI44L OAS1 0.915943 RIG1 IFI44SAMD9L 0.915918 IFI44 CHMP5 SP110 0.915791 PARP9 SP110 XIAP 0.915523RIG1 OAS1 RIGE 0.915317 OAS2 CIG5 XIAP 0.915027 IFIT5 IFI44L SAMD9L0.914239 IFI44L CHMP5 IFIT1 0.914106 IFIT5 IFI44 PARP9 0.913922 OAS1OAS3 SP110 0.913805 IFI44L OAS1 IFI44 0.913685 OAS2 G1P2 OAS3 0.913341OAS3 MX1 SP110 0.913024 MX1 RIGE ZBP1 0.91295 IFI44L IFI44 PARP90.912714 RIG1 CIG5 ZBP1 0.912402 IFIT5 HERC5 CHMP5 0.912293 IFIT4 SP110ZBP1 0.912203 CIG5 OAS3 PARP9 0.912168 IFIT5 G1P2 CHMP5 0.912138 IFIT4OAS3 ZBP1 0.912117 IFIT4 IFI44 CHMP5 0.912012 OAS2 RIG1 IRF7 0.911984IRF7 SP110 XIAP 0.911965 TYKI SP110 RIGE 0.9118 IFI44L HERC5 CHMP50.911777 OAS2 OAS3 MX1 0.91137 OAS2 G1P2 RIGE 0.911317 IFIT4 PARP9 RIGE0.911158 IFI44 CHMP5 XIAP 0.910766 OAS2 EPSTI1 CIG5 0.910517 OASL IRF7ZBP1 0.910488 OASL XIAP ZBP1 0.909994 IFI44L TYKI CHMP5 0.909904 EPSTI1PARP9 SP110 0.909711 IFI44 CHMP5 MX1 0.909689 IFIT5 TYKI CHMP5 0.90968G1P2 OASL RIGE 0.90961 IFI44L G1P2 CHMP5 0.909576 IFIT5 OAS1 IFI440.909388 IFIT4 CIG5 RIGE 0.908925 OAS2 OAS1 RIGE 0.908806 OAS2 HERC5RIGE 0.908751 OASL HERC5 RIGE 0.908541 CIG5 PARP9 SP110 0.908525 EPSTI1OASL ZBP1 0.908429 RIG1 OAS1 CHMP5 0.90836 IFI44L IFI44 SAMD9L 0.907964IRF7 IFI44 CHMP5 0.907863 CIG5 OAS3 XIAP 0.907513 IRF7 CIG5 OAS30.907333 IFIT4 OASL OAS3 0.906832 RIG1 OASL CIG5 0.90659 SAMD9L SP110RIGE 0.906569 EPSTI1 SP110 XIAP 0.906534 IFIT5 IFI44 SAMD9L 0.90643EPSTI1 CIG5 OAS3 0.906354 IFI44 CHMP5 IFIT1 0.906304 OASL MX1 RIGE0.906245 IRF7 PARP9 SP110 0.906101 EPSTI1 IRF7 SP110 0.906008 IFIT4 OASLSP110 0.905978 OAS2 MX1 RIGE 0.90518 CIG5 SP110 XIAP 0.90499 IFIT1 SP110RIGE 0.904324 IFI44 HERC5 CHMP5 0.904282 RIG1 OASL PARP9 0.904259 OAS3SAMD9L RIGE 0.904065 IFI44L OAS1 CHMP5 0.903581 IRF7 CIG5 SP110 0.903302G1P2 IFI44 CHMP5 0.903298 G1P2 SP110 RIGE 0.903287 OAS2 EPSTI1 RIG10.903249 OASL PARP9 ZBP1 0.902995 OAS2 OASL PARP9 0.902848 IFI44 TYKICHMP5 0.902228 OAS1 OASL RIGE 0.901099 OAS2 IRF7 ZBP1 0.900596 OAS2 RIG1PARP9 0.900166 OAS3 IFIT1 RIGE 0.900065 OASL CIG5 ZBP1 0.899594 EPSTI1RIGE XIAP 0.899556 IFIT5 OAS1 CHMP5 0.89953 OAS2 RIG1 XIAP 0.899013IFIT5 PARP9 CHMP5 0.898064 OAS2 OASL IRF7 0.898064 OAS3 TYKI RIGE0.897749 OAS2 EPSTI1 ZBP1 0.897534 IFIT4 RIG1 RIGE 0.897168 EPSTI1 RIG1OAS3 0.896978 OAS2 PARP9 ZBP1 0.896335 IFIT4 RIGE ZBP1 0.896273 OAS1IFI44 CHMP5 0.896108 IFIT5 IFI44L RIG1 0.895894 IFI44L PARP9 CHMP50.895497 IFIT4 OAS2 OAS3 0.895401 OAS2 EPSTI1 OASL 0.895303 OAS2 OASLXIAP 0.895129 HERC5 SP110 RIGE 0.894807 EPSTI1 CIG5 SP110 0.894768 IFIT4OAS2 SP110 0.894337 IRF7 RIGE XIAP 0.8943 RIG1 SAMD9L CHMP5 0.89381IFI44L SAMD9L CHMP5 0.893745 PARP9 RIGE XIAP 0.89358 OAS2 XIAP ZBP10.893376 EPSTI1 IRF7 RIGE 0.893012 EPSTI1 PARP9 RIGE 0.892978 IFIT5SAMD9L CHMP5 0.892943 RIG1 PARP9 ZBP1 0.892935 CIG5 RIGE XIAP 0.892719IFIT4 OAS3 SP110 0.891861 MX1 SP110 RIGE 0.891301 OAS3 HERC5 RIGE0.891101 RIG1 IRF7 OAS3 0.890525 OAS2 RIG1 CIG5 0.890495 EPSTI1 OAS3ZBP1 0.890069 OAS1 OAS3 RIGE 0.89006 IFI44L RIG1 IFI44 0.88778 IFIT5IFI44L IFI44 0.88776 RIG1 OAS3 XIAP 0.887549 IFI44 PARP9 CHMP5 0.887524G1P2 OAS3 RIGE 0.887416 EPSTI1 CIG5 RIGE 0.887118 OAS2 CIG5 ZBP10.886902 OAS1 SP110 RIGE 0.88684 CIG5 PARP9 RIGE 0.886773 OAS2 OASL CIG50.886112 IFI44 SAMD9L CHMP5 0.885956 IFIT4 OASL RIGE 0.885918 IFIT5 RIG1IFI44 0.885817 IRF7 CIG5 RIGE 0.885643 IRF7 OAS3 ZBP1 0.885583 OAS3 MX1RIGE 0.885561 EPSTI1 OASL OAS3 0.883489 IRF7 SP110 ZBP1 0.883248 OAS3XIAP ZBP1 0.883087 RIG1 PARP9 CHMP5 0.882158 IFIT4 OAS2 RIGE 0.881223SP110 XIAP ZBP1 0.881076 OASL OAS3 PARP9 0.880696 OAS3 PARP9 ZBP10.880421 RIG1 IRF7 SP110 0.880086 EPSTI1 SP110 ZBP1 0.879636 RIG1 OASLZBP1 0.879626 IRF7 PARP9 RIGE 0.87949 OASL OAS3 XIAP 0.879447 RIG1 SP110XIAP 0.879006 OASL IRF7 OAS3 0.878692 RIG1 OAS3 PARP9 0.878538 OASLSP110 XIAP 0.876723 OASL PARP9 SP110 0.875724 RIG1 CIG5 OAS3 0.875511CIG5 OAS3 ZBP1 0.875241 OASL IRF7 SP110 0.874351 PARP9 SP110 ZBP10.873999 OAS2 OAS3 PARP9 0.873713 CIG5 SP110 ZBP1 0.873581 IFIT5 IFI44LCHMP5 0.873435 EPSTI1 OASL SP110 0.872477 OAS2 EPSTI1 OAS3 0.872405 OAS2PARP9 SP110 0.87155 EPSTI1 RIG1 SP110 0.871342 OASL CIG5 OAS3 0.870785RIG1 CIG5 SP110 0.869263 EPSTI1 RIGE ZBP1 0.868804 IFIT4 OAS3 RIGE0.868713 OASL CIG5 SP110 0.867945 IFI44L IFI44 CHMP5 0.867675 OAS2 IRF7OAS3 0.867456 IFIT5 IFI44 CHMP5 0.867157 RIGE XIAP ZBP1 0.866861 IFI44LRIG1 CHMP5 0.864815 OAS2 IRF7 SP110 0.863904 IFIT5 RIG1 CHMP5 0.863765OAS2 OAS3 XIAP 0.862892 OAS2 OASL ZBP1 0.862277 EPSTI1 OAS3 SP1100.861466 IRF7 RIGE ZBP1 0.861372 OAS3 PARP9 SP110 0.861136 EPSTI1 RIG1RIGE 0.860936 IFIT4 SP110 RIGE 0.860801 RIG1 RIGE XIAP 0.860302 OAS2EPSTI1 SP110 0.860174 CIG5 RIGE ZBP1 0.859596 OAS2 SP110 XIAP 0.858564EPSTI1 OASL RIGE 0.857914 OAS2 RIG1 OASL 0.857565 OASL RIGE XIAP0.857553 OAS2 CIG5 OAS3 0.857493 IRF7 OAS3 SP110 0.857288 OAS3 SP110XIAP 0.856743 RIG1 IFI44 CHMP5 0.855689 OAS2 RIG1 ZBP1 0.85545 RIG1PARP9 SP110 0.855367 OAS2 CIG5 SP110 0.854157 OAS2 EPSTI1 RIGE 0.852592PARP9 RIGE ZBP1 0.852095 OASL CIG5 RIGE 0.850683 RIG1 CIG5 RIGE 0.850622OASL IRF7 RIGE 0.849649 CIG5 OAS3 SP110 0.849016 OAS2 RIGE XIAP 0.848472OASL PARP9 RIGE 0.847797 RIG1 IRF7 RIGE 0.847049 OAS2 PARP9 RIGE 0.84672OAS2 IRF7 RIGE 0.844908 OASL OAS3 ZBP1 0.843861 OAS2 CIG5 RIGE 0.84326EPSTI1 OAS3 RIGE 0.843087 OASL SP110 ZBP1 0.840384 OAS3 RIGE XIAP0.835809 RIG1 OAS3 ZBP1 0.835232 CIG5 OAS3 RIGE 0.830689 IRF7 OAS3 RIGE0.830055 RIG1 OASL OAS3 0.829875 OAS3 PARP9 RIGE 0.829849 RIG1 PARP9RIGE 0.827293 RIG1 SP110 ZBP1 0.827103 OAS2 OAS3 ZBP1 0.825923 OAS2 OASLOAS3 0.825647 EPSTI1 SP110 RIGE 0.824627 SP110 RIGE XIAP 0.823548 OASLRIGE ZBP1 0.821675 OAS2 SP110 ZBP1 0.821066 OAS2 OASL SP110 0.820454CIG5 SP110 RIGE 0.819918 RIG1 OASL SP110 0.818533 OAS3 SP110 ZBP10.814438 IRF7 SP110 RIGE 0.814248 PARP9 SP110 RIGE 0.812561 OAS2 RIGEZBP1 0.810229 OASL OAS3 SP110 0.809037 RIG1 RIGE ZBP1 0.806619 OAS2 OASLRIGE 0.804693 OAS2 RIG1 OAS3 0.803515 OAS3 RIGE ZBP1 0.79653 RIG1 OASLRIGE 0.79316 OASL OAS3 RIGE 0.789533 OAS2 OAS3 SP110 0.789077 OAS2 RIG1SP110 0.78802 RIG1 OAS3 SP110 0.785883 SP110 RIGE ZBP1 0.781728 OAS2RIG1 RIGE 0.777652 OAS2 OAS3 RIGE 0.7757 OASL SP110 RIGE 0.772656 RIG1OAS3 RIGE 0.761256 OAS2 SP110 RIGE 0.75784 OAS3 SP110 RIGE 0.7529 RIG1SP110 RIGE 0.725531

1-19. (canceled)
 20. A method of identifying a metric value correlatedwith presence and/or extent of an autoimmune disorder in a subject orsample, said method comprising: (a) estimating a group of probesets thatis collectively associated with a pattern wherein expression of genesrepresented by the probesets is associated with a diseasecharacteristic; (b) generating a weighting factor that weight probesetsin accordance with a scale reflecting extent of match of each individualprobeset to trend of the group of probesets, and calculating thecorrelation coefficient of each probeset's profile to the mean profilecalculated; (c) determining a scaling factor, wherein the scaling factoris the value required to scale individual probesets to 1; (d)multiplying the scaling factor by the weighting factor to generate acomposite factor (e) multiplying a normal blood sample's signatures withthe composite factor, and averaging the resulting values across bothprobesets and samples to generate an average value, and inverting theaverage value to yield a global scaling factor; (f) multiplying eachweighting factor by the global scaling factor to obtain a vector ofscalar values, and multiplying the scalar values by an expressionsignature from a sample of interest, and averaging the resulting valuesto yield a single metric that is indicative of degree of gene expressionassociated with Type I interferons in the sample.
 21. The method ofclaim 20, wherein in step (a), the group of probesets comprisesprobesets that include, or cluster around, the coremost-tightly-correlated pair of probesets in subcluster associated witha disease characteristic.
 22. The method of claim 20, wherein in step(b), the factor is generated by transforming expression data of thegroup of probesets into z-scores comprising mean scaling to 1, base-2log transformation, then scaling to a standard deviation of the meanof
 1. 23. The method of claim 20, wherein in step (e), the globalscaling factor is useful for transforming output of the average ofprobesets from a sample of interest into a metric, wherein the metric is1 if the sample is from a normal, healthy subject.
 24. The method ofclaim 20, wherein the group of probesets comprises at least 2 of thoselisted in Table 1, 2, and/or
 3. 25. The method of claim 20, wherein thegroup of probesets comprises those listed in Table 1, 2, and/or
 3. 26. Amethod of predicting responsiveness of a human subject with systemiclupus erythematosus (SLE) to autoimmune disease therapy, said methodcomprising (a) performing a nucleic acid-based detection assay to detectmRNA expression level of at least three genes comprising a three genecombination listed in Table 4B in cells of a blood sample from the humansubject, wherein the at least three genes do not comprise OASL, IRF7 andPARP9; (b) determining that the cells from the human subject express theat least three genes comprising the three gene combination at a levelgreater than the expression level of the respective genes in cells of ablood sample from a healthy human control; thereby predicting that thehuman subject will have a favorable response to the autoimmune diseasetherapy, wherein the autoimmune disease therapy comprises ananti-interferon-alpha antibody or an anti-interferon-alpha receptorantibody.
 27. A method of treating a human subject having systemic lupuserythematosus (SLE), comprising: (a) performing a nucleic acid-baseddetection assay to detect mRNA expression levels of at least three genescomprising a three gene combination listed in Table 4B in cells of ablood sample from the human subject, wherein the at least three genes donot comprise OASL, IRF7 and PARP9; (b) determining that the cells fromthe human subject express the at least three genes comprising the threegene combination at a level greater than the expression level of therespective genes in cells of a blood sample from a healthy humancontrol; and (c) administering an effective amount of ananti-interferon-alpha antibody or an anti-interferon-alpha receptorantibody to the human subject expressing the at least three genescomprising the three gene combination at a level greater than theexpression level of the respective genes in cells of a blood sample froma healthy human control, thereby treating SLE in the human subject. 28.The method of claim 26, wherein the three gene combination comprises anythree genes of the group consisting of EPSTI1, HERC5, TYKI, IFI44L,CIG5, and IFI44.
 29. The method of claim 26, wherein the three genecombination is a combination selected from the group consisting of: (1)EPSTI1, HERC, and TYKI; (2) EPSTI1, HERC, and IFI44L; (3) EPSTI1, HERC,and CIG5; (4) EPSTI1, HERC, and IFI44; (5) HERC, TYKI, and IFI44L; (6)HERC, TYKI, and CIG5; (7) HERC, TYKI, and IFI44; (8) TYKI, IFI44L, andCIG5; (9) TYKI, IFI44L, and IFI44; (10) TYKI, IFI44L, and EPSTI1; (11)IFI44L, CIG5, and IFI44; (12) IFI44L, CIG5, and EPSTI1; (13) IFI44L,CIG5, and HERC; (14) IFI44L, CIG5, and TYKI; (15) CIG5, IFI44, andEPSTI1; (16) CIG5, IFI44, and HERC, (17) CIG5, IFI44, and TYKI, (18)IFI44, EPSTI1, and TYKI, (19) IFI44, EPSTI1, and IFI44L, and (20) IFI44,EPSTI1, and CIG5.


30. The method of claim 26, wherein the three gene combination isEPSTI1, HERC5 and TYKI.
 31. The method of claim 26, wherein theperforming a nucleic acid-based detection assay comprises performing anucleic acid hybridization assay.
 32. The method of claim 26, whereinthe performing a nucleic acid-based detection assay comprisingperforming a nucleic acid amplification assay.
 33. The method of claim26, wherein the autoimmune disease therapy comprises ananti-interferon-alpha antibody.
 34. The method of claim 27, wherein thethree gene combination comprises any three genes of the group consistingof EPSTI1, HERC5, TYKI, IFI44L, CIG5, and IFI44.
 35. The method of claim27, wherein the three gene combination is EPSTI1, HERC5 and TYKI. 36.The method of claim 27, wherein the performing a nucleic acid-baseddetection assay comprises performing a nucleic acid hybridization assay.37. The method of claim 27, wherein the performing a nucleic acid-baseddetection assay comprising performing a nucleic acid amplificationassay.
 38. The method of claim 27, wherein step (c) comprisesadministering the anti-interferon-alpha antibody to the human subject.39. The method of claim 38, wherein step (c) comprises administering theanti-interferon-alpha antibody to the human subject in combination witha second therapeutic agent.
 40. The method of claim 39, wherein thesecond therapeutic agent is a steroid.